CN105294592A - Amine compound preparation method - Google Patents
Amine compound preparation method Download PDFInfo
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- CN105294592A CN105294592A CN201510794814.1A CN201510794814A CN105294592A CN 105294592 A CN105294592 A CN 105294592A CN 201510794814 A CN201510794814 A CN 201510794814A CN 105294592 A CN105294592 A CN 105294592A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
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Abstract
The present invention provides an amine compound preparation method, and belongs to the technical field of pharmacy. The method comprises that 2-amino-4-chlorophenol and a tetraethyl orthoformate reagent are subjected to a condensation reaction in the presence of an acid catalyst, the obtained compound and a solvent are mixed, and the obtained mixture and N-tert-butoxycarbonyl ethylenediamine or a salt thereof are subjected to a substitution reaction under an acid reagent adding condition so as to prepare the target amine compound. The method of the present invention has characteristics of mild reaction conditions, simple operation, environmental protection, easy production control, and high purity product obtaining, and is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical technology sectors, be specifically related to the preparation method of a kind of amine compound for the preparation of orexin receptor antagonists.
Background technology
Orexin (orexins) is the neuropeptide that a class is produced by hypothalamus neurons, by the direct projection of nerve fiber or discharge into ventricles of the brain circulation, by activate two kinds with cell surface receptor---the orexin receptor (OX1R and OX2R) of G-protein coupling, transmitting the clear-headed message of various maintenance to human body, is therefore the arch-criminal causing people to have a sleepless night.
Compound shown in following formula (I), English name is Suvorexant, the chemistry chloro-2-{ of 5-(5R)-5-methyl 4-[5-methyl-2-(2H-1 by name; 2,3-triazole-2-base) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-base }-1; 3-benzoxazole
Be a kind of diazepan compounds of replacement, by Merck, company develops, and in August, 2014 to get the Green Light listing in the U.S., is the newtype drug being used for the treatment of or preventing neurological caused by orexin receptor and psychiatric disturbance and disease.
Amine compound (02) as shown in the formula shown in (02):
It is a kind of important intermediate for the preparation of compound (I).In the prior art, as in the disclosed methods such as patent application WO2013169610, need to use comparatively harsh reaction conditions, or react comparatively very complicated, or need the reaction reagent etc. that use toxicity is larger, be unfavorable for suitability for industrialized production.Therefore, need to develop that a kind of raw material is easy to get, easy and simple to handle, simple, the eco-friendly method preparing amine compound (02) being suitable for suitability for industrialized production.
Summary of the invention
Summary of the invention
The invention provides the method that one prepares intermediate amine compound (02), it is reaction mass that its method comprises use orthoformic acid four ester class reagent, through reactions such as replacements, and obtained compound (02).
Term definition
In the present invention, described Boc is tertbutyloxycarbonyl.
Detailed Description Of The Invention
The invention provides the method that one prepares amine compound (02), shown method reaction conditions is simple.One prepares the method for compound (02), it comprises: carry out condensation reaction with orthoformic acid four ester class reagent in presence of an acid catalyst as shown in the formula the compound (00) shown in (00), obtained as shown in the formula the compound (01) shown in (01); Compound (01) and solvent, carry out substitution reaction with N-tertbutyloxycarbonyl quadrol or its salt adding under sour reagent conditions, obtained compound (02); Reaction scheme is as follows:
Wherein, R is methyl or ethyl.
Described orthoformic acid four ester class reagent is orthoformic acid four methyl esters or orthoformic acid tetra-ethyl ester.
The mol ratio of orthoformic acid four ester class reagent and compound (00) is 1.0:1-2.0:1, and in certain embodiments, the mol ratio of orthoformic acid four ester class reagent and compound (00) is 1.0:1-1.8:1.In certain embodiments, the mol ratio of orthoformic acid four ester class reagent and compound (00) is 1.02:1-1.3:1.
Described acid catalyst is acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid, citric acid, or its combination.In some embodiments, described acid catalyst is phosphoric acid, hydrochloric acid, sulfuric acid, tosic acid, or methylsulfonic acid.In some embodiments, described acid catalyst is phosphoric acid.
The mol ratio of acid catalyst and compound (00) is 0.001:1-0.5:1.In some embodiments, the mol ratio of acid catalyst and compound (00) is 0.005:1-0.5:1.In some embodiments, the mol ratio of acid catalyst and compound (00) is 0.005:1-0.25:1.
The temperature of reaction of described condensation reaction is 20 DEG C-120 DEG C.In some embodiments, the temperature of reaction of described condensation reaction is 40 DEG C-100 DEG C.In some embodiments, the temperature of reaction of described condensation reaction is 55 DEG C-90 DEG C.In some embodiments, the temperature of reaction of described condensation reaction is 60 DEG C-90 DEG C.
The reaction times of described condensation reaction is 1 hour-5 hours.In some embodiments, the reaction times of described condensation reaction is 1 hour-3 hours.
After described condensation reaction terminates, solid can be collected, except obtaining compound (01) after desolventizing after reaction system adds water stirring for some time.Describedly can carry out at 20 DEG C-120 DEG C or use the method such as vacuum-drying or forced air drying except desolventizing.
In some embodiments, compound (00) and orthoformic acid tetra-ethyl ester carry out condensation reaction 1 hour-3 hours at 55 DEG C-90 DEG C under phosphoric acid exists, then reaction solution is cooled to 5 DEG C-30 DEG C, add water, stir 0.1 hour-1 hour, collect solid, except desolventizing, obtained compound (01).
Describedly prepare in the method for compound (02), after obtained compound (01), by compound (01) and solvent, described solvent is ethyl acetate, methyl tertiary butyl ether, acetone, methylene dichloride, acetonitrile, tetrahydrofuran (THF), normal hexane, hexanaphthene, 1, one or more in 4-dioxane, toluene, DMF.In some embodiments, by compound (01) and solvent, described solvent is hexanaphthene.
In described substitution reaction, sour reagent is acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methylsulfonic acid, tosic acid, or its combination.In some embodiments, described sour reagent is acetic acid.The mol ratio of acid reagent and compound (01) is 0.05:1-0.5:1.In some embodiments, the mol ratio of sour reagent and compound (01) is 0.05:1-0.25:1.
In described substitution reaction, the mol ratio of N-tertbutyloxycarbonyl quadrol and compound (01) is 1:1-2:1.In some embodiments, the mol ratio of N-tertbutyloxycarbonyl quadrol and compound (01) is 1.05:1-1.5:1.
The temperature of reaction of described substitution reaction is 50 DEG C-120 DEG C.In some embodiments, the temperature of reaction of described substitution reaction is 60 DEG C-120 DEG C.In some embodiments, the temperature of reaction of described substitution reaction is 70 DEG C-100 DEG C.In some embodiments, the temperature of reaction of described substitution reaction is 70 DEG C-90 DEG C.
The reaction times of described substitution reaction is 4 hours-20 hours.In some embodiments, the reaction times of described substitution reaction is 6 hours-16 hours.In some embodiments, the reaction times of described substitution reaction is 8 hours-14 hours.
After described substitution reaction terminates, by aftertreatment as being cooled to 0 DEG C-30 DEG C, then collecting solid, reaction solvent washed product can be used if desired, then except desolventizing, obtain compound (02).
In described substitution reaction, vacuum drying method at solid is placed in 35 DEG C-100 DEG C can be adopted to remove desolventizing.
In some embodiments, compound (01) mixes with hexanaphthene, is adding under acetic acid condition, carries out substitution reaction 6 hours-16 hours with N-tertbutyloxycarbonyl quadrol or its salt at 70 DEG C-90 DEG C, obtained compound (02).
Describedly prepare in the method for compound (02), described condensation reaction, substitution reaction can proceed step by step, first be separated and obtain compound (01), then compound (02) is prepared, also one kettle way can be adopted to carry out, do not isolate midbody compound (01).
In some embodiments, described condensation reaction, substitution reaction adopt one kettle way to carry out, it comprises: by compound (00) in presence of an acid catalyst with orthoformic acid four ester class reagent condensation reaction 1 hour-3 hours, without aftertreatment, then solvent, sour reagent and N-tertbutyloxycarbonyl quadrol is added directly to reaction system, at 40 DEG C-120 DEG C, carry out substitution reaction, then obtain midbody compound (02) through aftertreatment.
The method preparing compound (02) of the present invention, adopt orthoformic acid four ester as condensation reaction reagent, effectively prevent the phosgene using severe toxicity, and reaction conditions is gentle, easy and simple to handle, environmental friendliness, is easy to production control, the product of higher degree can be obtained with high yield, be suitable for suitability for industrialized production.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, g represents gram, and mL represents milliliter.
Embodiment 1
In reaction flask, add 2-amino-4-chlorophenol 14.40g, original methyl carbonate 23.10g and acetic acid 0.60g.Be heated to 50 DEG C, temperature control stirring 3 hours.Then be cooled to 10 DEG C, add water 120mL in reaction system, stir 0.5 hour, filter, filter cake washes 3 times with water, each 30mL.Gained solid, in 40 DEG C of vacuum-dryings, obtains solid 18.50g, is compound (01), purity >99%.
Embodiment 2
In reaction flask, add 2-amino-4-chlorophenol 14.40g, tetraethyl orthocarbonate 21.16g and phosphoric acid 0.12g, stir, be heated to 80 DEG C and stir 1.5 hours.Then be cooled to 15 DEG C, add water 150mL, stir 0.5 hour.Filter, filter cake washes 3 times with water, each 30mL.Gained solid, in 40 DEG C of vacuum-dryings, obtains khaki color solid 18.54g, is compound (01), purity >99%.
Embodiment 3
In reaction flask, add 2-amino-4-chlorophenol 14.40g, tetraethyl orthocarbonate 28.85g and phosphoric acid 0.07g, stir, be heated to 60 DEG C and stir 2 hours.Then be cooled to 10 DEG C, add water 200mL, stir 1 hour.Filter, filter cake washes 3 times with water, each 30mL.Gained solid, in 50 DEG C of vacuum-dryings, obtains khaki color solid 18.55g, is compound (01), purity >99%.
Embodiment 4
In reaction flask, add compound (01) 3.30g, dissolve, add N-tertbutyloxycarbonyl quadrol 3.80g, methylsulfonic acid 0.40g respectively with 40mL toluene, 120 DEG C are stirred 8 hours.Then be down to 20 DEG C, filter, gained solid toluene 30mL washs once, and 60 DEG C of vacuum-dryings, obtain pink solid compound (02) 4.91g, purity >99%.
Embodiment 5
In reaction flask, add compound (01) 3.30g, add 50mL normal hexane, stir, add N-tertbutyloxycarbonyl quadrol 4.00g, and trifluoroacetic acid 0.20g, reflux stirs 8 hours.Then be cooled to 10 DEG C, filter, gained solid n-hexane 3 times, each 10mL, then 40 DEG C of vacuum-dryings, obtain compound (02) 4.94g, purity >99%.
Embodiment 6
In reaction flask, add compound (01) 3.30g, add 40mL hexanaphthene, stir, add N-tertbutyloxycarbonyl quadrol 3.20g, and glacial acetic acid 0.10g, be heated to outer temperature 85 DEG C and stir 10 hours.Then be cooled to 20 DEG C, filter, gained solid hexanaphthene washs 3 times, each 10mL, and then 50 DEG C of vacuum-dryings are to dry, obtain compound (02) 4.97g, purity >99%.
Embodiment 7
2-amino-4-chlorophenol 14.40g is added, tetraethyl orthocarbonate 28.90g and tosic acid 3.40g, stirring reaction 4 hours at 80 DEG C in reaction flask.Then reaction system is cooled to 40 DEG C, in reaction system, add 80mL methyl tertiary butyl ether and N-tertbutyloxycarbonyl quadrol 3.20g, return stirring reacts 14 hours.Then be cooled to 20 DEG C, filter, filter cake methyl tertiary butyl ether 30mL washs, and obtains compound (02) 4.90g, purity >99% after the vacuum-drying of gained solid.
Embodiment 8
2-amino-4-chlorophenol 14.40g is added, tetraethyl orthocarbonate 28.90g and phosphoric acid 0.15g, stirring reaction 4 hours at 80 DEG C in reaction flask.Then reaction system is cooled to 30 DEG C, in reaction system, adds 100mL hexanaphthene and N-tertbutyloxycarbonyl quadrol 3.20g, reflux stirring reaction 14 hours.Then be cooled to 20 DEG C, filter, filter cake hexanaphthene 20mL washs, and obtains compound (02) 4.93g, purity >99% after the vacuum-drying of gained solid.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (10)
1. prepare the method for compound (02) for one kind, comprise: carry out condensation reaction with orthoformic acid four ester class reagent in presence of an acid catalyst as shown in the formula the compound (00) shown in (00), obtained as shown in the formula the compound (01) shown in (01); Compound (01) and solvent, carry out substitution reaction with N-tertbutyloxycarbonyl quadrol or its salt adding under sour reagent conditions, obtained compound (02),
Wherein, R is methyl or ethyl; Described orthoformic acid four ester class reagent is orthoformic acid four methyl esters or orthoformic acid tetra-ethyl ester.
2. method according to claim 1, described acid catalyst is acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid, citric acid, or its combination.
3. method according to claim 1, the mol ratio of described acid catalyst and compound (00) is 0.001:1-0.5:1.
4. method according to claim 1, the temperature of reaction of described condensation reaction is 40 DEG C-100 DEG C.
5. method according to claim 1, described solvent is ethyl acetate, methyl tertiary butyl ether, acetone, methylene dichloride, acetonitrile, tetrahydrofuran (THF), normal hexane, hexanaphthene, 1, one or more in 4-dioxane, toluene, DMF.
6. method according to claim 1, described sour reagent is acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methylsulfonic acid, tosic acid, or its combination; The mol ratio of described sour reagent and compound (01) is 0.05:1-0.5:1.
7. method according to claim 1, the temperature of reaction of described substitution reaction is 50 DEG C-120 DEG C.
8. method according to claim 1, compound (00) and orthoformic acid tetra-ethyl ester carry out condensation reaction 1 hour-3 hours at 55 DEG C-90 DEG C under phosphoric acid exists, then reaction solution is cooled to 5 DEG C-30 DEG C, add water, stir 0.1 hour-1 hour, collect solid, except desolventizing, obtained compound (01).
9. method according to claim 1, compound (01) mixes with hexanaphthene, adding under acetic acid condition, carrying out substitution reaction 6 hours-16 hours with N-tertbutyloxycarbonyl quadrol or its salt at 70 DEG C-90 DEG C, obtained compound (02).
10. method according to claim 1, does not isolate compound (01).
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| CN201510794814.1A CN105294592B (en) | 2015-11-18 | 2015-11-18 | A kind of preparation method of amines |
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| CN201510794814.1A CN105294592B (en) | 2015-11-18 | 2015-11-18 | A kind of preparation method of amines |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015008218A2 (en) * | 2013-07-15 | 2015-01-22 | Dr. Reddy’S Laboratories Limited | Process for the preparation of suvorexant and intermediates useful in the synthesis of suvorexant |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015008218A2 (en) * | 2013-07-15 | 2015-01-22 | Dr. Reddy’S Laboratories Limited | Process for the preparation of suvorexant and intermediates useful in the synthesis of suvorexant |
Non-Patent Citations (2)
| Title |
|---|
| CHRISTOPHER L ET AL.: "Synthesis of 2-Aminobenzoxazoles Using Tetramethyl Orthocarbonate or 1,1-Dichlorodiphenoxymethane", 《J. ORG. CHEM》 * |
| GAVIN W ET AL.: "A Mild and Efficient One-Pot Synthesis of 2-Aminated Benzoxazoles and Benzothiazoles", 《J. ORG. CHEM》 * |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |
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