CN105294592B - A kind of preparation method of amines - Google Patents
A kind of preparation method of amines Download PDFInfo
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- CN105294592B CN105294592B CN201510794814.1A CN201510794814A CN105294592B CN 105294592 B CN105294592 B CN 105294592B CN 201510794814 A CN201510794814 A CN 201510794814A CN 105294592 B CN105294592 B CN 105294592B
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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 invention provides a kind of preparation method of amines, belong to pharmaceutical technology field.Methods described includes the chlorophenol of 2 amino 4 and the esters reagent of orthoformic acid four carrying out condensation reaction in presence of an acid catalyst, then gained compound with solvent by mixing, substitution reaction is carried out with N tertbutyloxycarbonyls ethylenediamine or its salt under the conditions of acid reagent is added, target amines is made.The method reaction condition of the present invention is gentle, easy to operate, environment-friendly, is readily produced control, can obtain the product of higher degree, be suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to for preparing a kind of amines of orexin receptor antagonists
Preparation method.
Background technology
Orexin (orexins) is one kind neuropeptide as caused by hypothalamus neurons, passes through the direct throwing of nerve fibre
Ventricles of the brain circulation is penetrated or discharges into, by activating two kinds of cell surface receptor --- orexin receptor (OX1R being coupled with G-protein
And OX2R), the various messages for keeping regaining consciousness are transmitted to human body, therefore be the arch-criminal for causing people to have a sleepless night.
Compound shown in lower formula (I), English name Suvorexant, the entitled chloro- 2- of 5- { (the 5R) -5- methyl of chemistry
4- [5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl] -1,4- Diazesuberane -1- bases } -1,3- Ben Bing Evil
Azoles,
It is a kind of substituted diazepan compounds, is developed by United States Merck company, in August, 2014 is in the U.S.
Get the Green Light listing, is for treating or preventing neurology and psychiatric disturbance and disease caused by orexin receptor
Newtype drug.
Amines (02) as shown in following formula (02)：
It is a kind of important intermediate for prepare compound (I).In the prior art, such as patent application
In method disclosed in WO2013169610 etc., it is necessary to using more harsh reaction condition, or the relatively complicated complexity of reaction, or
Person needs to use larger reaction reagent of toxicity etc., is unfavorable for industrialized production.Therefore it is easy to get, grasps, it is necessary to develop a kind of raw material
Make easy, simple, the environment-friendly method for preparing amines (02) suitable for industrialized production.
The content of the invention
Summary of the invention
The present invention provides the method that one kind prepares intermediate amine compound (02), and its method is including the use of the esters of orthoformic acid four
Reagent is reaction mass, and by the reaction such as substitution, compound (02) is made.
Term defines
In the present invention, the Boc is tertbutyloxycarbonyl.
Detailed description of the invention
The invention provides the method that one kind prepares amines (02), shown method reaction condition is simple.It is prepared by one kind
The method of compound (02), it includes：Compound (00) as shown in following formula (00) in presence of an acid catalyst with orthoformic acid four
Esters reagent carries out condensation reaction, and the compound (01) as shown in following formula (01) is made；Compound (01) mixes with solvent, is adding
Enter and carry out substitution reaction with N- tertbutyloxycarbonyls ethylenediamine or its salt under the conditions of acid reagent, compound (02) is made；Reaction scheme
It is as follows：
Wherein, R is methyl or ethyl.
The esters reagent of orthoformic acid four is the methyl esters of orthoformic acid four or orthoformic acid tetra-ethyl ester.
The mol ratio of the esters reagent of orthoformic acid four and compound (00) is 1.0:1-2.0:1, in certain embodiments, primitive nail
The mol ratio of sour four esters reagents and compound (00) is 1.0:1-1.8:1.In certain embodiments, the esters reagent of orthoformic acid four
Mol ratio with compound (00) is 1.02:1-1.3:1.
The acid catalyst is acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, citric acid,
Or its combination.In some embodiments, the acid catalyst is phosphoric acid, hydrochloric acid, sulfuric acid, p-methyl benzenesulfonic acid, or methanesulfonic acid.
In some embodiments, the acid catalyst is phosphoric acid.
The mol ratio of acid catalyst and compound (00) is 0.001:1-0.5:1.In some embodiments, acid catalyst
Mol ratio with compound (00) is 0.005:1-0.5:1.In some embodiments, acid catalyst and compound (00) are rubbed
You are than being 0.005:1-0.25:1.
The reaction temperature of the condensation reaction is 20 DEG C -120 DEG C.In some embodiments, the condensation reaction is anti-
It is 40 DEG C -100 DEG C to answer temperature.In some embodiments, the reaction temperature of the condensation reaction is 55 DEG C -90 DEG C.At some
In embodiment, the reaction temperature of the condensation reaction is 60 DEG C -90 DEG C.
The reaction time of the condensation reaction is -5 hours 1 hour.In some embodiments, the condensation reaction is anti-
It is -3 hours 1 hour between seasonable.
After the condensation reaction terminates, solid is collected after water stirring a period of time can be added to reaction system, removes solvent
After obtain compound (01).The removing solvent can be carried out either using vacuum drying or forced air drying etc. at 20 DEG C -120 DEG C
Method.
In some embodiments, compound (00) is carried out with orthoformic acid tetra-ethyl ester in the presence of phosphoric acid at 55 DEG C -90 DEG C
Condensation reaction -3 hours 1 hour, reaction solution is then cooled to 5 DEG C -30 DEG C, adds water, stirred -1 hour 0.1 hour, collected
Solid, solvent is removed, compound (01) is made.
In the method for the prepare compound (02), after compound (01) is made, compound (01) is mixed with solvent, institute
Solvent is stated as ethyl acetate, methyl tertiary butyl ether(MTBE), acetone, dichloromethane, acetonitrile, tetrahydrofuran, n-hexane, hexamethylene, 1,4-
One or more in dioxane, toluene, N,N-dimethylformamide.In some embodiments, by compound (01) with
Solvent mixes, and the solvent is hexamethylene.
In the substitution reaction, acid reagent be acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, to toluene sulphur
Acid, or its combination.In some embodiments, the acid reagent is acetic acid.Acid reagent and the mol ratio of compound (01) are
0.05:1-0.5:1.In some embodiments, the mol ratio of acid reagent and compound (01) is 0.05:1-0.25:1.
In the substitution reaction, the mol ratio of N- tertbutyloxycarbonyls ethylenediamine and compound (01) is 1:1-2:1.At some
In embodiment, the mol ratio of N- tertbutyloxycarbonyls ethylenediamine and compound (01) is 1.05:1-1.5:1.
The reaction temperature of the substitution reaction is 50 DEG C -120 DEG C.In some embodiments, the substitution reaction is anti-
It is 60 DEG C -120 DEG C to answer temperature.In some embodiments, the reaction temperature of the substitution reaction is 70 DEG C -100 DEG C.At some
In embodiment, the reaction temperature of the substitution reaction is 70 DEG C -90 DEG C.
The reaction time of the substitution reaction is -20 hours 4 hours.In some embodiments, the substitution reaction
Reaction time is -16 hours 6 hours.In some embodiments, the reaction time of the substitution reaction is -14 hours 8 hours.
After the substitution reaction terminates, 0 DEG C -30 DEG C can be such as cooled to by post processing, then collect solid, if necessary may be used
Using reaction dissolvent washed product, solvent is then removed, obtains compound (02).
In the substitution reaction, it can use and solid is placed in vacuum drying method removing solvent at 35 DEG C -100 DEG C.
In some embodiments, compound (01) mixes with hexamethylene, under the conditions of acetic acid is added, with N- tertiary butyloxycarbonyls
Base ethylenediamine or its salt carry out substitution reaction -16 hours 6 hours at 70 DEG C -90 DEG C, and compound (02) is made.
In the method for the prepare compound (02), described condensation reaction, substitution reaction can be carried out step by step, first be separated
Compound (01) is obtained, compound (02) is then prepared, one kettle way can also be used to carry out, not isolate intermediate compound
Thing (01).
In some embodiments, described condensation reaction, substitution reaction are carried out using one kettle way, and it includes：By chemical combination
Thing (00) in presence of an acid catalyst with four esters reagent condensation reaction of orthoformic acid -3 hours 1 hour, without post processing, then
Solvent, acid reagent and N- tertbutyloxycarbonyl ethylenediamines directly are added to reaction system, substitution reaction is carried out at 40 DEG C -120 DEG C,
Then midbody compound (02) is obtained by post processing.
The method of prepare compound (02) of the present invention, using the ester of orthoformic acid four as condensation reaction reagent, effectively
The phosgene using severe toxicity is avoided, and reaction condition is gentle, it is easy to operate, it is environment-friendly, control is readily produced, high can be received
The product of higher degree is obtained to rate, is suitable for industrialized production.
Embodiment
In order that those skilled in the art more fully understands technical scheme, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention can from the market be bought or can be by method system described in the invention
It is standby and obtain.
In the present invention, g expressions gram, mL represents milliliter.
Embodiment 1
In reaction bulb, 2- amino -4- chlorophenol 14.40g, original methyl carbonate 23.10g and acetic acid 0.60g are added.Add
Hot to 50 DEG C, temperature control stirring 3 hours.Then 10 DEG C are cooled to, water 120mL is added into reaction system, is stirred 0.5 hour, mistake
Filter, filter cake are washed with water 3 times, each 30mL.Gained solid obtains solid 18.50g, is compound in 40 DEG C of vacuum drying
(01), purity>99%.
Embodiment 2
2- amino -4- chlorophenol 14.40g, tetraethyl orthocarbonate 21.16g and phosphoric acid 0.12g are added in reaction bulb, is stirred
Mix, be heated to 80 DEG C and stir 1.5 hours.Then 15 DEG C are cooled to, adds water 150mL, is stirred 0.5 hour.Filtering, filter cake water
Washing 3 times, each 30mL.Gained solid is dried in vacuo in 40 DEG C, is obtained khaki solid 18.54g, is compound (01), pure
Degree>99%.
Embodiment 3
2- amino -4- chlorophenol 14.40g, tetraethyl orthocarbonate 28.85g and phosphoric acid 0.07g are added in reaction bulb, is stirred
Mix, be heated to 60 DEG C and stir 2 hours.Then 10 DEG C are cooled to, adds water 200mL, is stirred 1 hour.Filtering, filter cake are washed with water
3 times, each 30mL.Gained solid obtains khaki solid 18.55g, is compound (01) in 50 DEG C of vacuum drying, purity>
99%.
Embodiment 4
Compound (01) 3.30g is added in reaction bulb, is dissolved with 40mL toluene, is separately added into N- tertbutyloxycarbonyls second two
Amine 3.80g, methanesulfonic acid 0.40g, 120 DEG C are stirred 8 hours.Then 20 DEG C are down to, filtering, gained solid washs one with toluene 30mL
It is secondary, 60 DEG C of vacuum drying, obtain pink solid compound (02) 4.91g, purity>99%.
Embodiment 5
Compound (01) 3.30g is added in reaction bulb, 50mL n-hexanes is added, stirring, adds N- tertbutyloxycarbonyl second
Diamines 4.00g, and trifluoroacetic acid 0.20g, it is heated to reflux stirring 8 hours.Then 10 DEG C are cooled to, filtering, gained solid is with just
Hexane washs 3 times, each 10mL, and then 40 DEG C of vacuum drying, obtain compound (02) 4.94g, purity>99%.
Embodiment 6
Compound (01) 3.30g is added in reaction bulb, 40mL hexamethylenes is added, stirring, adds N- tertbutyloxycarbonyl second
Diamines 3.20g, and glacial acetic acid 0.10g, it is heated to outer 85 DEG C of temperature and stirs 10 hours.Then 20 DEG C are cooled to, is filtered, gained solid
3 times, each 10mL are washed with hexamethylene, and then 50 DEG C are dried under vacuum to dry, obtain compound (02) 4.97g, purity>99%.
Embodiment 7
2- amino -4- chlorophenol 14.40g, tetraethyl orthocarbonate 28.90g and p-methyl benzenesulfonic acid are added in reaction bulb
3.40g, stirring reaction 4 hours at 80 DEG C.Then reaction system is cooled to 40 DEG C, 80mL methyl- terts is added into reaction system
Butyl ether and N- tertbutyloxycarbonyl ethylenediamine 3.20g, return stirring react 14 hours.Then 20 DEG C are cooled to, filtering, filter cake is used
Methyl tertiary butyl ether(MTBE) 30mL is washed, and compound (02) 4.90g, purity are obtained after the vacuum drying of gained solid>99%.
Embodiment 8
Add 2- amino -4- chlorophenol 14.40g, tetraethyl orthocarbonate 28.90g and phosphoric acid 0.15g in reaction bulb, 80
Stirring reaction 4 hours at DEG C.Then reaction system is cooled to 30 DEG C, 100mL hexamethylenes and uncle N- is added into reaction system
Butoxy carbonyl ethylenediamine 3.20g, is heated to reflux stirring reaction 14 hours.Then 20 DEG C are cooled to, is filtered, filter cake hexamethylene
20mL is washed, and compound (02) 4.93g, purity are obtained after the vacuum drying of gained solid>99%.
The present invention method be described by preferred embodiment, related personnel substantially can present invention,
Method described herein and application are modified or suitably changed with combining in spirit and scope, to realize and using the present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, institute
Have similar replacement and change it is apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (6)
1. a kind of method of prepare compound (02), including：Compound (00) as shown in following formula (00) exists in acid catalyst
The lower and esters reagent of orthoformic acid four carries out condensation reaction -5 hours 1 hour, after condensation reaction terminates, is stirred to reaction system plus water
Solid is collected after a period of time, the compound (01) as shown in following formula (01) is made；Compound (01) mixes with solvent, is adding
Substitution reaction is carried out with N- tertbutyloxycarbonyls ethylenediamine or its salt under the conditions of acid reagent, reaction system is then cooled to 0 DEG C -30
DEG C, solid is collected, reaction dissolvent washed product can be used if necessary, then remove solvent, compound (02) is made,
Wherein, R is methyl or ethyl；The esters reagent of orthoformic acid four is the methyl esters of orthoformic acid four or orthoformic acid tetra-ethyl ester；It is described
Acid catalyst is phosphoric acid, hydrochloric acid, sulfuric acid, p-methyl benzenesulfonic acid, or methanesulfonic acid；The acid catalyst and the mol ratio of compound (00)
For 0.001:1-0.5:1；The acid reagent is acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, or
It is combined；The mol ratio of the acid reagent and compound (01) is 0.05:1-0.5:1.
2. according to the method for claim 1, the reaction temperature of the condensation reaction is 40 DEG C -100 DEG C.
3. according to the method for claim 1, the solvent be ethyl acetate, methyl tertiary butyl ether(MTBE), acetone, dichloromethane,
One or more in acetonitrile, tetrahydrofuran, n-hexane, hexamethylene, 1,4- dioxane, toluene, N,N-dimethylformamide.
4. according to the method for claim 1, the reaction temperature of the substitution reaction is 50 DEG C -120 DEG C.
5. the method according to claim 11, compound (00) and orthoformic acid tetra-ethyl ester are in the presence of phosphoric acid at 55 DEG C -90 DEG C
Condensation reaction -3 hours 1 hour is carried out, reaction solution is then cooled to 5 DEG C -30 DEG C, adds water, is stirred -1 hour 0.1 hour,
Solid is collected, removes solvent, compound (01) is made.
6. according to the method for claim 1, compound (01) mixes with hexamethylene, under the conditions of acetic acid is added, with uncle N-
Butoxy carbonyl ethylenediamine or its salt carry out substitution reaction -16 hours 6 hours at 70 DEG C -90 DEG C, and compound (02) is made.
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| Application Number | Priority Date | Filing Date | Title |
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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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| CN105294592A CN105294592A (en) | 2016-02-03 |
| CN105294592B true CN105294592B (en) | 2018-01-23 |
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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- 2015-11-18 CN CN201510794814.1A patent/CN105294592B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| A Mild and Efficient One-Pot Synthesis of 2-Aminated Benzoxazoles and Benzothiazoles;Gavin W et al.;《J. Org. Chem》;20090324;第74卷;3229-3231 * |
| Synthesis of 2-Aminobenzoxazoles Using Tetramethyl Orthocarbonate or 1,1-Dichlorodiphenoxymethane;Christopher L et al.;《J. Org. Chem》;20101025;第75卷(第22期);7942-7945 * |
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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. |