CN109206381A - A kind of preparation method adjusting the movable compound intermediate of Cannabined receptor - Google Patents
A kind of preparation method adjusting the movable compound intermediate of Cannabined receptor Download PDFInfo
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- CN109206381A CN109206381A CN201811031825.4A CN201811031825A CN109206381A CN 109206381 A CN109206381 A CN 109206381A CN 201811031825 A CN201811031825 A CN 201811031825A CN 109206381 A CN109206381 A CN 109206381A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
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Abstract
The invention discloses a kind of preparation method for adjusting the movable compound intermediate of Cannabined receptor, IV compound of formula is prepared through acyl chloride reaction in VI compound of formula by S1.；S2. III compound of formula is prepared through aminating reaction in V compound of formula；S3. II compound of formula is prepared through cyclization reaction in IV compound of formula and III compound of formula；S4. type I compound is prepared through reduction reaction in II compound of formula.Operation of the present invention is simple, and raw material is easy to get, and side reaction is few, and the three wastes are few, and production cost is low, does not utilize noxious material, environmentally protective to the corrosion-damaged smaller of equipment, and obtained intermediate yield is high.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to it is living that one kind can directly or indirectly adjust Cannabined receptor CB2
The preparation method of dynamic compound intermediate.
Background technique
Cannboid is active constituent present in cunjah, and including about 6 kinds of different molecules, one of the most common is
Tetrahydrocannabinol.Before 5000, hemp is just used to treat asthma, migraine and gynecological disease by ancient Chinese.1850,
Cannador is recognized and is put into United States Pharmacopeia.
It is well known that cannboid has different influences to many functions and organ, it is most important that Central nervous system
And cardiovascular system.These influence to include the change remembered, floaty euphoria and sedation.Cannboid can also enhance pulse, change
Systemic arterial pressure.It can also be observed that with bronchoconstriction, the peripheral effect of immunological regulation and inflammation-related.Research table recently
It is bright, the adjustable cell of cannboid and humoral immune reaction, and there is anti-inflammatory effect.Although cannboid has these good spies
Property, but cannboid still has dispute using upper in treatment, because they have positive effect (the reason of dependence) to spirit, and
Their multiple side effect determines completely not yet.Since the forties in last century, researcher carries out in this field
A large amount of research, but to the feature of Cannabined receptor, endogenic ligand there are few important breakthroughs, nearest recent studies on
The information of special receptor subtype-selective product is also seldom.
It has now been discovered that and having cloned two kinds of Cannabined receptors: CB1 and CB2.CB1 is mainly in central nervous system table
It reaches, and CB2 is mainly expressed in immune system peripheral tissues.The two receptors are the receptor family members in conjunction with G-protein, suppression
It makes of related with the activity of adenyl cyclase.
According to these information, there is a kind of demand of compound, this compound can be selectively adjusted cannboid
Receptor, to adjust pathology relevant to this receptor.CB2 regulator be immunologic derangement, inflammation, osteoporosis, renal ischaemia and
Other pathological states provide single drug treatment.Researchers have very strong affinity to CB2 receptor in exploitation
Cannabinoid analogs in terms of produce very big interest.Cannabinoid analogs can directly or indirectly adjust CB2 receptor, not
It influences to generate clinical useful effect in the case where central nervous system, to provide reasonable treatment for a variety of pathological states
Method.
A kind of new compound is needed, this compound can regulate and control the activity of CB2 and to treatment and prevention and cannboid
The relevant pathological state of receptor active and disease are effective, such as, but not limited to, which the disease of cell Proliferation such as cancer is immunized
Disease, inflammation, pain, osteoporosis, atherosclerosis, epilepsy, nausea and chemotherapy, fibrosis, intestines problem, nerve move back
Row disease includes multiple sclerosis and dyskinesia, Parkinson's disease, Huntington's chorea, Alzheimer disease, but is also used for
Prevention or treatment disease related with motor function, such as Gilles de Ia Tourette syndrome, and neuroprotection is provided.
A kind of synthesis for adjusting the movable compound intermediate of Cannabined receptor is given in US20100056507 patent
Route, specific synthetic route are as follows:
It is easy to produce impurity in the synthesis process of the synthetic route, the disadvantages of low yield, severe reaction conditions, the time is long, in order to
Overcome disadvantages mentioned above, the present invention provides a kind of preparation methods for adjusting the movable compound intermediate of Cannabined receptor.
Summary of the invention
The purpose of the present invention is to provide it is a kind of adjust the movable compound intermediate of Cannabined receptor preparation method, with
The synthesis process of above-mentioned patent is compared, and noxious material is not utilized, and the damage to equipment is smaller, easy to operate, environmentally protective, is obtained
The intermediate yield arrived is high.
The preparation method of cannabinoid analogs intermediate of the present invention, comprising the following steps:
S1. VI compound of formula, solvent are added in reaction flask, stirring is slowly added dropwise chloroacetic chloride, is added dropwise, slowly after heating
It is stirred to react, solvent is concentrated under reduced pressure and obtains IV compound of formula；
S2. middle V compound of addition formula, solvent in reaction flask, stirring, are added the aqueous solution of hydrazine hydrate, and it is anti-to be heated to reflux
It answers, system is transferred in single port bottle, revolving removes solvent and obtains III compound of formula；
S3. III compound of formula, IV compound of formula and solvent, heating reflux reaction, after reaction, by body are added in there-necked flask
It is that solution is transferred in single port bottle, revolving removes extra solvent, and obtained solid is placed in a vacuum drying oven and is dried to obtain slightly
Product；
S4. solvent, graphite are added in reaction flask, is added with stirring NH2NH2.H2O is heated to reflux, after reaction, filtering,
Filter cake organic solvent washing collects filtrate, and revolving obtains solid, is placed in drying in vacuum oven, obtains product；
Further, organic solvent required for the acyl chloride reaction in step S1 is methanol, ethyl alcohol, at least one in isopropanol
Kind.
Further, the acyl chloride reaction in step S1 reacts 40~50h at 20~30 DEG C.
Further, the R in IV compound of formula in step S11For-Et ,-Me ,- i At least one of Pr.
Further, organic solvent required for the aminating reaction in step S2 be methanol, ethyl alcohol, in toluene, dimethylbenzene
It is at least one.
Further, the 15~30h of back flow reaction at 70~90 DEG C of the aminating reaction in step S2.
Further, the R in V compound of formula in step S22For-OCH3、-OCH2CH3At least one of.
Further, solvent required for the cyclization reaction in step S3 is ethyl alcohol；At 80~100 DEG C back flow reaction 3~
10h。
Further, organic solvent required for the reduction reaction in step S4 is methanol, ethyl alcohol, isopropanol, cyclohexanol, third
At least one of alcohol；70~80h of back flow reaction at 60~100 DEG C.
Further, the product being prepared is used to adjust the activity of Cannabined receptor, reduces the injury to human body spirit.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated, but it is not intended to limit implementation of the invention.
Embodiment 1
The preparation of compounds Ⅳ:
In reaction flask, 5,5,8,8- tetramethyls -5,6 are added, 7,8- tetrahydronaphthalene -2- formonitrile HCNs (17g), ethyl alcohol (20ml) will
Mixture stirs evenly, and temperature is controlled at 3 DEG C, and chloroacetic chloride (46ml) is slowly added dropwise.After being added dropwise, temperature is slowly increased to 25
DEG C, be stirred to react 43h at such a temperature, with TLC contact plate detect extent of reaction, to the end of after, be concentrated under reduced pressure solvent.By gained
Solid is placed in vacuum oven dry, the Weighed product 26.13g after cooling, yield 75%.
Embodiment 2
The preparation of compounds Ⅳ:
In reaction flask, 5,5,8,8- tetramethyls -5,6 are added, 7,8- tetrahydronaphthalene -2- formonitrile HCNs (17g), ethyl alcohol (20ml) will
Mixture stirs evenly, and temperature is controlled at 3 DEG C, and chloroacetic chloride (46ml) is slowly added dropwise.After being added dropwise, temperature is slowly increased to 30
DEG C, be stirred to react 48h at such a temperature, with TLC contact plate detect extent of reaction, to the end of after, be concentrated under reduced pressure solvent.By gained
Solid is placed in vacuum oven dry, the Weighed product 28.23g after cooling, yield 81.02%.
Embodiment 3
The preparation of compound III:
In reaction flask, 3- (4- nitrobenzophenone) propionic acid (11.7g, 60mmol), ethyl alcohol (100ml) is added, stirs the mixture for
After uniformly, the aqueous solution (16ml, 80%) of hydrazine hydrate is added, after temperature rises to 75 DEG C, back flow reaction 20h is detected with TLC contact plate
System is transferred in single port bottle by extent of reaction after complete reaction, is placed in a vacuum drying oven after revolving removing solvent dry
It is dry.Weigh 28.94g, yield 81.84%.The MS/LC of compound III and1H NMR data MS/LC:m/z=209.0878(M+H+).
NMR(1H, 400MHz, DMSO): δ 2.36(t, 2H), 2.96(t, 2H) and, 4.15(s, 2H), 7.46(AB, 2H), 8.14(AB,
2H), 8.96(s, 1H).
Embodiment 4
The preparation of compound III:
In reaction flask, 3- (4- nitrobenzophenone) propionic acid (11.7g, 60mmol), ethyl alcohol (100ml) is added, stirs the mixture for
After uniformly, the aqueous solution (16ml, 80%) of hydrazine hydrate is added, after temperature rises to 85 DEG C, back flow reaction 28h is detected with TLC contact plate
System is transferred in single port bottle by extent of reaction after complete reaction, is placed in a vacuum drying oven after revolving removing solvent dry
It is dry.Weigh 30.06g, yield 85.01%.The MS/LC of compound III and1H NMR data MS/LC:m/z=209.0878(M+H+).
NMR(1H, 400MHz, DMSO): δ 2.36(t, 2H), 2.96(t, 2H) and, 4.15(s, 2H), 7.46(AB, 2H), 8.14(AB,
2H), 8.96(s, 1H).
Embodiment 5
The preparation of compound ii:
In 100ml there-necked flask, III compound of 10.5g formula, IV compound of 14.7g formula, 200ml absolute ethanol, temperature liter is added
To after 85 DEG C, back flow reaction 5h, TLC contact plate is detected after reaction, and system solution is transferred in single port bottle, and revolving is removed more
Remaining solvent, obtained solid is placed in a vacuum drying oven and is dried to obtain crude product.Crude product obtains sterling through column chromatography for separation.Claim
Weight 16.38g, yield 81.29%.The MS/LC of compound ii and1H NMR data: MS/LC:m/z=405.4898(M+H+).NMR
(1H, 400MHz, DMSO): δ 1.21；1.24(2s, 12H), 1.65(s, 4H), 3.28(t, 2H) and, 3.37(t, 2H), 7.51(AB,
1H), 7.59(AB, 2H), 7.68(AB, 1H), 7.74(s, 1H) and, 8.13(AB, 2H).
Embodiment 6
The preparation of compound ii:
In 100ml there-necked flask, III compound of 10.5g formula, IV compound of 14.7g formula, 200ml absolute ethanol, temperature liter is added
To after 95 DEG C, back flow reaction 8h, TLC contact plate is detected after reaction, and system solution is transferred in single port bottle, and revolving is removed more
Remaining solvent, obtained solid is placed in a vacuum drying oven and is dried to obtain crude product.Crude product obtains sterling through column chromatography for separation.Claim
Weight 17.51g, yield 86.9%.The MS/LC of compound ii and1H NMR data: MS/LC:m/z=405.4898(M+H+).NMR
(1H, 400MHz, DMSO): δ 1.21；1.24(2s, 12H), 1.65(s, 4H), 3.28(t, 2H) and, 3.37(t, 2H), 7.51(AB,
1H), 7.59(AB, 2H), 7.68(AB, 1H), 7.74(s, 1H) and, 8.13(AB, 2H).
Embodiment 7
The preparation of chemical compounds I:
4.9g(12mmol is added in reaction flask) II compound of formula, 60mL isopropanol, 7.2g(300mmol) graphite, under stirring
3gNH is added2NH2.H2O, after temperature rises to 80 DEG C, back flow reaction 70h, TLC detect filtering after reaction, filter cake dichloro
Methane wash collects filtrate, and revolving obtains solid, is placed in vacuum oven dry.Products therefrom 2.93g, yield 78.47%.
The MS/LC of chemical compounds I and1H NMR data: MS/LC:m/z=375.2309(M+H+).NMR(1H, 400MHz, DMSO): δ 1.24
(2s, 12H), 1.66(s, 4H), 2.96(t, 2H), 3.11(t, 2H) and, 4.87(s, 2H), 6.43(AB, 1H) and, 6.91(AB, 2H),
7.56(AB, 1H), 7.70(AB, 1H), 7.82(s, 1H).
Embodiment 8
The preparation of chemical compounds I:
4.9g(12mmol is added in reaction flask) II compound of formula, 60mL absolute ethanol, 7.2g(300mmol) graphite, stirring
Lower addition 3gNH2NH2.H2O, after temperature rises to 90 DEG C, back flow reaction 78h, TLC detect filtering after reaction, and filter cake is with two
Filtrate is collected in chloromethanes washing, and revolving obtains solid, is placed in vacuum oven dry.Products therefrom 3.14g, yield
84.09%.The MS/LC of chemical compounds I and1H NMR data: MS/LC:m/z=375.2309(M+H+).NMR(1H, 400MHz,
DMSO): δ 1.24(2s, 12H), 1.66(s, 4H), 2.96(t, 2H), 3.11(t, 2H) and, 4.87(s, 2H), 6.43(AB, 1H),
6.91(AB, 2H), 7.56(AB, 1H), 7.70(AB, 1H) and, 7.82(s, 1H).
Claims (10)
1. a kind of preparation method for adjusting the movable compound intermediate of Cannabined receptor, which comprises the following steps:
S1. VI compound of formula, solvent are added in reaction flask, stirring is slowly added dropwise chloroacetic chloride, is added dropwise, slowly after heating
It is stirred to react, solvent is concentrated under reduced pressure and obtains IV compound of formula；
S2. middle V compound of addition formula, solvent in reaction flask, stirring, are added the aqueous solution of hydrazine hydrate, and it is anti-to be heated to reflux
It answers, system is transferred in single port bottle, revolving removes solvent and obtains III compound of formula；
S3. III compound of formula, IV compound of formula and solvent, heating reflux reaction, after reaction, by body are added in there-necked flask
It is that solution is transferred in single port bottle, revolving removes extra solvent, and obtained solid is placed in a vacuum drying oven and is dried to obtain slightly
Product；
S4. solvent, graphite are added in reaction flask, is added with stirring NH2NH2.H2O is heated to reflux, after reaction, filtering,
Filter cake organic solvent washing collects filtrate, and revolving obtains solid, is placed in drying in vacuum oven, obtains product；
。
2. the preparation method according to claim 1 for adjusting the movable compound intermediate of Cannabined receptor, feature exist
In: organic solvent required for the acyl chloride reaction in step S1 is at least one of methanol, ethyl alcohol, isopropanol.
3. the preparation method according to claim 1 for adjusting the movable compound intermediate of Cannabined receptor, feature exist
In: the acyl chloride reaction in step S1 reacts 40~50h at 20~30 DEG C.
4. the preparation method according to claim 1 for adjusting the movable compound intermediate of Cannabined receptor, feature exist
In: the R in IV compound of formula in step S11For-Et ,-Me ,- i At least one of Pr.
5. the preparation method according to claim 1 for adjusting the movable compound intermediate of Cannabined receptor, feature exist
In: organic solvent required for the aminating reaction in step S2 be methanol, ethyl alcohol, at least one of toluene, dimethylbenzene.
6. the preparation method according to claim 1 for adjusting the movable compound intermediate of Cannabined receptor, feature exist
In: aminating reaction in step S2 15~30h of back flow reaction at 70~90 DEG C.
7. the preparation method according to claim 1 for adjusting the movable compound intermediate of Cannabined receptor, feature exist
In: the R in V compound of formula in step S22For-OCH3、-OCH2CH3At least one of.
8. the preparation method according to claim 1 for adjusting the movable compound intermediate of Cannabined receptor, feature exist
In: solvent required for the cyclization reaction in step S3 is ethyl alcohol；3~10h of back flow reaction at 80~100 DEG C.
9. the preparation method according to claim 1 for adjusting the movable compound intermediate of Cannabined receptor, feature exist
In: organic solvent required for the reduction reaction in step S4 be methanol, ethyl alcohol, isopropanol, cyclohexanol, at least one in propyl alcohol
Kind；70~80h of back flow reaction at 60~100 DEG C.
10. the preparation method of the adjusting movable compound intermediate of Cannabined receptor according to claims 1 to 9, special
Sign is: the product being prepared is used to adjust the activity of Cannabined receptor, reduces the injury to human body spirit.
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