CN109206381B - A method for preparing compound intermediate for regulating activity of cannabinoid receptor - Google Patents
A method for preparing compound intermediate for regulating activity of cannabinoid receptor Download PDFInfo
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- CN109206381B CN109206381B CN201811031825.4A CN201811031825A CN109206381B CN 109206381 B CN109206381 B CN 109206381B CN 201811031825 A CN201811031825 A CN 201811031825A CN 109206381 B CN109206381 B CN 109206381B
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- 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
Abstract
The invention discloses a preparation method of a compound intermediate for regulating activity of a cannabinoid receptor, which comprises the following steps of S1, carrying out acyl chlorination on a compound shown in a formula VI to prepare a compound shown in a formula IV; s2, carrying out amination reaction on the compound of the formula V to prepare a compound of a formula III; s3, carrying out cyclization reaction on the compound of the formula IV and the compound of the formula III to prepare a compound of a formula II; and S4, carrying out reduction reaction on the compound of the formula II to obtain the compound of the formula I. The method has the advantages of simple operation, easily obtained raw materials, less side reaction, less three wastes, low production cost, no utilization of toxic substances, less corrosion damage to equipment, environmental protection and high yield of the obtained intermediate.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a preparation method of a compound intermediate capable of directly or indirectly regulating activity of cannabinoid receptor CB 2.
Background
Cannabinoids are the active ingredients present in cannabis sativa, including approximately 6 different molecules, the most common of which is tetrahydrocannabinol. Cannabis was used in ancient times in china as early as 5000 years ago for the treatment of asthma, migraine and gynecological diseases. In 1850, cannabis extracts were approved and listed in the United states pharmacopoeia.
Cannabinoids are known to have diverse effects on many functions and organs, most importantly on the central nervous system and cardiovascular system. These effects include changes in memory, euphoria, and sedation. Cannabinoids also enhance the pulse and alter systemic arterial pressure. Peripheral effects associated with bronchoconstriction, immunomodulation and inflammation were also observed. Recent studies have shown that cannabinoids can modulate cellular and humoral immune responses and have anti-inflammatory effects. Despite these good properties, cannabinoids remain controversial in therapeutic use because they have a positive mental effect (the cause of dependence) and their multiple side effects have not yet been fully established. Since the last 40 s, researchers have conducted extensive research in this area, but there have been few major breakthroughs in the characteristics of cannabinoid receptors, the presence of endogenous ligands, and little information recently on specific receptor subtype-selective products of new research.
Two cannabinoid receptors have now been discovered and cloned: CB1 and CB 2. CB1 is expressed predominantly in the central nervous system, whereas CB2 is expressed predominantly in peripheral tissues of the immune system. These two receptors are members of the family of receptors that bind to G proteins, and their inhibition is associated with adenylate cyclase activity.
Based on this information, there is a need for compounds that selectively modulate cannabinoid receptors and thereby modulate pathologies associated with such receptors. CB2 modulators provide a single drug treatment for immune disorders, inflammation, osteoporosis, renal ischemia and other pathological conditions. Researchers have generated much interest in developing cannabinoid analogs with strong affinity for the CB2 receptor. Cannabinoid analogs can modulate CB2 receptors directly or indirectly, producing clinically useful effects without affecting the central nervous system, and thus provide rational treatment for a variety of pathological conditions.
There is a need for novel compounds that can modulate the activity of CB2 and have effects in the treatment and prevention of pathological conditions and diseases associated with cannabinoid receptor activity, such as, but not limited to, diseases of cell proliferation such as cancer, immune disorders, inflammation, pain, osteoporosis, atherosclerosis, epilepsy, nausea and chemotherapy, fibrosis, intestinal disorders, neurodegenerative disorders including multiple sclerosis and dyskinesia, parkinson's disease, huntington's chorea, alzheimer's disease, but also in the prevention or treatment of diseases associated with motor function such as tourette's syndrome, and to provide neuroprotection.
A synthetic route to intermediates of compounds that modulate activity of cannabinoid receptors is given in US20100056507 patent as follows:
the synthetic process of the synthetic route has the defects of easy generation of impurities, low yield, harsh reaction conditions, long time and the like, and in order to overcome the defects, the invention provides a preparation method of a compound intermediate for regulating activity of a cannabinoid receptor.
Disclosure of Invention
The invention aims to provide a preparation method of a compound intermediate for regulating activity of a cannabinoid receptor, compared with the synthesis process of the patent, the preparation method does not utilize toxic substances, has less damage to equipment, is simple to operate, is green and environment-friendly, and has high yield of the obtained intermediate.
The preparation method of the cannabinoid analogue intermediate comprises the following steps:
s1, adding a compound of formula VI and a solvent into a reaction bottle, stirring, slowly dropwise adding acetyl chloride, after dropwise adding, slowly heating, stirring for reaction, and concentrating the solvent under reduced pressure to obtain a compound of formula IV;
s2, adding a compound of the formula V and a solvent into a reaction bottle, stirring, adding a hydrazine hydrate aqueous solution, heating to reflux reaction, transferring the system into a single-mouth bottle, and removing the solvent by rotary evaporation to obtain a compound of the formula III;
s3, adding a compound of a formula III, a compound of a formula IV and a solvent into a three-mouth bottle, heating and refluxing for reaction, transferring a system solution into a single-mouth bottle after the reaction is finished, removing the redundant solvent by rotary evaporation, and drying the obtained solid in a vacuum drying oven to obtain a crude product;
s4, adding the solvent and the graphite into a reaction bottle, and adding NH while stirring2NH2.H2Heating and refluxing, filtering after the reaction is finished, washing a filter cake by using an organic solvent, collecting filtrate, carrying out rotary evaporation to obtain a solid, and drying in a vacuum drying oven to obtain a product;
further, the solvent used in the reaction in step S1 is any one of methanol, ethanol, and isopropanol.
Further, the reaction in the step S1 is carried out for 40-50 h at 20-30 ℃.
Further, R in the compound of formula IV in step S11is-Et, -Me-iPr.
Further, the solvent used in the reaction in step S2 is at least one of methanol, ethanol, toluene, and xylene.
Further, the reaction in the step S2 is performed with reflux reaction for 15-30 h at 70-90 ℃.
Further, R in the compound of formula V in step S22is-OCH3、-OCH2CH3Any one of them.
Further, the solvent required for the cyclization reaction in step S3 is ethanol; reflux reaction is carried out for 3-10 h at 80-100 ℃.
Further, the solvent required for the reduction reaction in step S4 is at least one of methanol, ethanol, isopropanol, cyclohexanol, and propanol; reflux reaction is carried out for 70-80 h at 60-100 ℃.
Further, the obtained product is used for regulating activity of cannabinoid receptor and reducing harm to human spirit.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the practice of the invention.
Example 1
Preparation of Compound IV:
5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalene-2-carbonitrile (17g) and ethanol (20ml) were added to a reaction flask, and the mixture was stirred well, while controlling the temperature at 3 ℃ and acetyl chloride (46ml) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 25 ℃ and the reaction was stirred at this temperature for 43h, the progress of the reaction was checked by TLC spot plate and, after completion, the solvent was concentrated under reduced pressure. The solid obtained was placed in a vacuum oven to dry, and after cooling the product weighed 26.13g, giving a yield of 75%.
Example 2
Preparation of Compound IV:
5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalene-2-carbonitrile (17g) and ethanol (20ml) were added to a reaction flask, and the mixture was stirred well, while controlling the temperature at 3 ℃ and acetyl chloride (46ml) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to 30 ℃, the reaction was stirred at the temperature for 48 hours, the progress of the reaction was checked by TLC spot plate, and after completion, the solvent was concentrated under reduced pressure. The resulting solid was placed in a vacuum oven to dry until after cooling the product weighed 28.23g, giving a yield of 81.02%.
Example 3
Preparation of compound iii:
adding 3- (4-nitrophenyl) propionic acid (11.7g and 60mmol) and ethanol (100ml) into a reaction bottle, stirring the mixture uniformly, adding a hydrazine hydrate aqueous solution (16ml and 80%), heating to 75 ℃, carrying out reflux reaction for 20 hours, detecting the progress of the reaction by using a TLC (thin layer chromatography) spot plate, transferring the system into a single-neck bottle after the reaction is completed, and drying in a vacuum drying oven after the solvent is removed by rotary evaporation. 28.94g was weighed, yield 81.84%. MS/LC of Compound III and1h NMR data MS/LC: 209.0878(M + H)+)。NMR(1H，400MHz，DMSO)：δ2.36(t，2H)，2.96(t，2H)，4.15(s，2H)，7.46(AB，2H)，8.14(AB，2H)，8.96(s，1H)。
Example 4
Preparation of compound iii:
adding 3- (4-nitrophenyl) propionic acid (11.7g and 60mmol) and ethanol (100ml) into a reaction bottle, stirring the mixture uniformly, adding a hydrazine hydrate aqueous solution (16ml and 80%), heating to 85 ℃, refluxing for 28h, detecting the reaction progress by using a TLC (thin layer chromatography) spot plate, transferring the system into a single-neck bottle after the reaction is completed, removing the solvent by rotary evaporation, and drying in a vacuum drying oven. 30.06g was weighed, yield 85.01%. MS/LC of Compound III and1h NMR data MS/LC: 209.0878 m/z(M+H+)。NMR(1H，400MHz，DMSO)：δ2.36(t，2H)，2.96(t，2H)，4.15(s，2H)，7.46(AB，2H)，8.14(AB，2H)，8.96(s，1H)。
Example 5
Preparation of compound ii:
and (3) adding 10.5g of a compound shown in the formula III, 14.7g of a compound shown in the formula IV and 200ml of absolute ethanol into a 100ml three-neck flask, heating to 85 ℃, carrying out reflux reaction for 5 hours, transferring the system solution into a single-neck flask after TLC (thin layer chromatography) spot plate detection reaction is finished, carrying out rotary evaporation to remove excessive solvent, and drying the obtained solid in a vacuum drying oven to obtain a crude product. And the crude product is separated by column chromatography to obtain a pure product. 16.38g was weighed, yield 81.29%. MS/LC of Compound II and1h NMR data: MS/LC: 405.4898(M + H)+)。NMR(1H，400MHz，DMSO)：δ1.21；1.24(2s，12H)，1.65(s，4H)，3.28(t，2H)，3.37(t，2H)，7.51(AB，1H)，7.59(AB，2H)，7.68(AB，1H)，7.74(s，1H)，8.13(AB，2H)。
Example 6
Preparation of compound ii:
and (3) adding 10.5g of a compound shown in the formula III, 14.7g of a compound shown in the formula IV and 200ml of absolute ethanol into a 100ml three-neck flask, heating to 95 ℃, performing reflux reaction for 8 hours, transferring the system solution into a single-neck flask after TLC (thin layer chromatography) spot plate detection reaction is finished, performing rotary evaporation to remove excessive solvent, and drying the obtained solid in a vacuum drying oven to obtain a crude product. And the crude product is separated by column chromatography to obtain a pure product. 17.51g were weighed, yield 86.9%. MS/LC of Compound II and1h NMR data: MS/LC: 405.4898(M + H)+)。NMR(1H，400MHz，DMSO)：δ1.21；1.24(2s，12H)，1.65(s，4H)，3.28(t，2H)，3.37(t，2H)，7.51(AB，1H)，7.59(AB，2H)，7.68(AB，1H)，7.74(s，1H)，8.13(AB，2H)。
Example 7
Preparation of compound i:
4.9g (12mmol) of the compound of the formula II, 60mL of isopropanol and 7.2g (300mmol) of graphite are introduced into a reaction flask, and 3g of NH are added with stirring2NH2.H2O, after the temperature is raised to 80 ℃,refluxing for 70h, filtering after TLC detection reaction, washing a filter cake with dichloromethane, collecting filtrate, performing rotary evaporation to obtain a solid, and drying in a vacuum drying oven. The product obtained was 2.93g, yield 78.47%. MS/LC of Compound I and1h NMR data: MS/LC: 375.2309(M + H)+)。NMR(1H，400MHz，DMSO)：δ1.24(2s，12H)，1.66(s，4H)，2.96(t，2H)，3.11(t，2H)，4.87(s，2H)，6.43(AB，1H)，6.91(AB，2H)，7.56(AB，1H)，7.70(AB，1H)，7.82(s，1H)。
Example 8
Preparation of compound i:
4.9g (12mmol) of the compound of the formula II, 60mL absolute ethanol, 7.2g (300mmol) of graphite are introduced into a reaction flask, and 3g of NH are added with stirring2NH2.H2And O, heating to 90 ℃, carrying out reflux reaction for 78h, filtering after TLC detection reaction is finished, washing a filter cake with dichloromethane, collecting filtrate, carrying out rotary evaporation to obtain a solid, and drying in a vacuum drying oven. The product was obtained 3.14g, yield 84.09%. MS/LC of Compound I and1h NMR data: MS/LC: 375.2309(M + H)+)。NMR(1H，400MHz，DMSO)：δ1.24(2s，12H)，1.66(s，4H)，2.96(t，2H)，3.11(t，2H)，4.87(s，2H)，6.43(AB，1H)，6.91(AB，2H)，7.56(AB，1H)，7.70(AB，1H)，7.82(s，1H)。
Claims (6)
1. A process for preparing a compound intermediate that modulates activity of cannabinoid receptors comprising the steps of:
s1, adding a compound of formula VI and a solvent into a reaction bottle, stirring, slowly dropwise adding acetyl chloride, after dropwise adding, slowly heating, stirring for reaction, and concentrating the solvent under reduced pressure to obtain a compound of formula IV; r in the Compound of formula IV in step S11Is any one of-Et, -Me and-iPr; in the step S1, the solvent is any one of methanol, ethanol and isopropanol;
s2, adding a compound of the formula V and a solvent into a reaction bottle, stirring, adding a hydrazine hydrate aqueous solution, heating to reflux reaction, transferring the system into a single-mouth bottle, and removing the solvent by rotary evaporation to obtain a compound of the formula III; r in the Compound of formula V in step S22
S3, adding a compound of a formula III, a compound of a formula IV and a solvent into a three-mouth bottle, heating and refluxing for reaction, transferring a system solution into a single-mouth bottle after the reaction is finished, removing the redundant solvent by rotary evaporation, and drying the obtained solid in a vacuum drying oven to obtain a crude product;
s4, adding the solvent and the graphite into a reaction bottle, and adding NH while stirring2NH2.H2Heating and refluxing, filtering after the reaction is finished, washing a filter cake by using an organic solvent, collecting filtrate, carrying out rotary evaporation to obtain a solid, and drying in a vacuum drying oven to obtain a product;
2. the process for the preparation of a compound intermediate that modulates the activity of cannabinoid receptors according to claim 1, characterized in that: the reaction in the step S1 is carried out for 40-50 h at 20-30 ℃.
3. The process for the preparation of a compound intermediate that modulates the activity of cannabinoid receptors according to claim 1, characterized in that: the solvent used in the reaction in step S2 is at least one of methanol, ethanol, toluene, and xylene.
4. The process for the preparation of a compound intermediate that modulates the activity of cannabinoid receptors according to claim 1, characterized in that: the reaction in the step S2 is performed with reflux reaction for 15-30 h at 70-90 ℃.
5. The process for the preparation of a compound intermediate that modulates the activity of cannabinoid receptors according to claim 1, characterized in that: the solvent in the cyclization reaction in the step S3 is ethanol; reflux reaction is carried out for 3-10 h at 80-100 ℃.
6. The process for the preparation of a compound intermediate that modulates the activity of cannabinoid receptors according to claim 1, characterized in that: in the reduction reaction in the step S4, the solvent is at least one of methanol, ethanol, isopropanol, cyclohexanol, and propanol; reflux reaction is carried out for 70-80 h at 60-100 ℃.
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| US7211594B2 (en) * | 2000-07-31 | 2007-05-01 | Signal Pharmaceuticals, Llc | Indazole compounds and compositions thereof as JNK inhibitors and for the treatment of diseases associated therewith |
| WO2008011557A2 (en) * | 2006-07-20 | 2008-01-24 | Borchardt Allen J | Heteroaryl inhibitors of rho kinase |
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| JP2014520858A (en) * | 2011-07-13 | 2014-08-25 | ノバルティス アーゲー | Novel 2-piperidin-1-yl-acetamide compounds for use as tankyrase inhibitors |
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