CN106478537A - A kind of preparation method of [2 [(5 chlorobenzene diozaiole, 2 base) (3 oxo butyl) amino] ethyl] t-butyl carbamate - Google Patents
A kind of preparation method of [2 [(5 chlorobenzene diozaiole, 2 base) (3 oxo butyl) amino] ethyl] t-butyl carbamate Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of [2 [(5 chlorobenzene diozaiole, 2 base) (3 oxo butyl) amino] ethyl] t-butyl carbamate, with ethylenediamine, butenone, 2 amino, 4 chlorophenol etc. as raw material, purpose product [2 [(5 chlorobenzene diozaiole, 2 base) (3 oxo butyl) amino] ethyl] t-butyl carbamate is obtained through the reaction of five steps.The present invention is easy to operate, environmental friendliness, and comprehensive yield is more than 52%, and more existing 35.6% yield, with being obviously improved, significantly reduces existing medicine production cost, is suitable for industrial-scale production.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of [2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo fourth
Base) amino] ethyl] and t-butyl carbamate preparation method.
Background technology
Suvorexant is used for treating sleep and dyscoimesis (insomnia) patient.Suvorexant is that a kind of orexin is received
Body antagonist, is first gets the Green Light in such medicine medicine.
[2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) amino] ethyl] t-butyl carbamate, molecular formula is
C18H24ClN3O4, molecular weight are 381.85386, and English name is tert-butyl2- ((5-chlorobenzo [d]
Oxazol-2-yl) (3-oxobutyl) aMino) ethylcarbaMate, it is an important intermediate of suvorexant.
As described in subsequent contrast's embodiment 1, existing synthesis technique, the total recovery of four-step reaction only have 35.6%, operation
Complexity, the low economic benefit of yield and ambient influnence be not good.
Content of the invention
For the above-mentioned deficiency of prior art, embodiments in accordance with the present invention, it is desirable to provide a kind of easy to operate, yield
Height, environmental friendliness, low production cost, are suitable for [2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo fourth of industrial-scale production
Base) amino] ethyl] and t-butyl carbamate preparation method.
According to embodiment, as shown in following synthetic route, one kind [2- [(chloro- benzoxazoles -2- of 5- that the present invention is provided
Base) (3- oxo butyl) amino] ethyl] and t-butyl carbamate preparation method, comprise the steps：
1) chloroform of di-tert-butyl dicarbonate, dioxane or tetrahydrofuran solution are instilled the phase of ethylenediamine at room temperature
Answering in the solution of solvent, stirring and terminate to reaction, water is added after being spin-dried for solvent, extracted with dichloromethane, organic layer merging is eaten
Salt is washed, and is dry, is spin-dried for obtaining N- tertbutyloxycarbonyl -1,2- ethylenediamine；
2) ehtyl potassium xanthate is added in the ethanol solution of 2- amino -4- chlorophenol, and is stirred at room temperature, then
Slow intensification is completed until reaction, and reaction mixture is poured in frozen water and is neutralized to neutrality with acid；Filter, filter residue successively with frozen water,
N-hexane is washed, and drying under reduced pressure obtains the chloro- 2- mercaptobenzoxazole of 5-；
3) thionyl chloride and N,N-dimethylformamide are added to the dichloro of the chloro- 2- mercaptobenzoxazole of 5- at 5-10 DEG C
In dichloromethane；After reaction solution is stirred at room temperature until reaction terminates, reactant liquor is poured in frozen water, is neutralized with sodium acid carbonate
To neutral, extracted with dichloromethane；Organic layer uses brine It after merging, and sodium sulphate dries, and is spin-dried for obtaining crude product, and the crude product is used
N-hexane is washed, and is filtered, is spin-dried for obtaining 2,5- dichloro benzoxazoles；
4) butenone is added drop-wise to N- tertbutyloxycarbonyl -1, in the diethyl ether solution of 2- ethylenediamine, stirring；Reactant liquor is cooled to 0
After DEG C, triethylamine and 2,5- dichloro benzoxazoles is sequentially added, stir and complete until reaction, product diluted ethyl acetate
Afterwards, successively with 10% citric acid, saturated sodium bicarbonate aqueous solution and saturated common salt water washing；Organic layer is dry with anhydrous sodium sulfate
Dry, filter, be spin-dried for [2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) amino] ethyl] t-butyl carbamate；
Step 1) in, the chloroform of di-tert-butyl dicarbonate, dioxane or tetrahydrofuran solution are instilled second at room temperature
In the solution of the coordinative solvent of diamines, refer to the chloroformic solution of di-tert-butyl dicarbonate is instilled the chloroform of ethylenediamine at room temperature
In solution, or the dioxane solution of di-tert-butyl dicarbonate is instilled in the dioxane solution of ethylenediamine at room temperature,
Or instill the tetrahydrofuran solution of di-tert-butyl dicarbonate in the tetrahydrofuran solution of ethylenediamine at room temperature.
Step 2) in, 2- amino -4- chlorophenol 3- (4- bromaniline) is 1: 1～1.6 with the mol ratio of ehtyl potassium xanthate；
Step 3) in, the chloro- 2- mercaptobenzoxazole of 5- is 1: 2～4 with the mol ratio of thionyl chloride；
Step 4) in, N- tertbutyloxycarbonyl -1,2- ethylenediamine are 1: 0.9～1.1 with the mol ratio of butenone.
According to embodiment, step 2) in, can be hydrochloric acid, glacial acetic acid, sulfuric acid, first for the acid of neutralization reaction mixed liquor
Acid, trifluoroacetic acid or oxalic acid.
After testing, nuclear magnetic spectrogram is as follows, it may be determined that final product is [2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo
Butyl) amino] ethyl] t-butyl carbamate.NMR(400MHz,CDCl3):δ 7.25 (d, 1H, J=2.2Hz), 7.10 (d,
1H, J-8.4Hz), 6.92 (dd, 1H, J=8.5,2.2Hz), 5.07 (s, 1H, br), 3.74 (t, 2H, J=6.6Hz), 3.64
(t, 2H, J=6.2Hz), 3.38 (d, 2H, br), 2.90 (t, 2H, J=6.8Hz), 2.15 (s, 3H), 1.34 (s, 9H).
Subsequent embodiment and comparative example may certify that the present invention has the advantages that：
1) comprehensive yield of the present invention is more than 57%, and more existing 35.6% yield, with being obviously improved, significantly drops
Low existing medicine production cost.
2) present invention optimizes preparation technology, greatly simplifies course of reaction and last handling process, simple to operate, significantly
Reduce production cost.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.These embodiments are interpreted as being merely to illustrate this
Bright rather than limit the scope of the invention.After the content for having read present invention record, those skilled in the art can
To make various changes or modifications to the present invention, these equivalence changes and modification equally fall into the model limited by the claims in the present invention
Enclose.
Embodiment 1
The first step：The synthesis of N- tertbutyloxycarbonyl -1,2- ethylenediamine.
Tetrahydrofuran (5L) solution of di-tert-butyl dicarbonate (545g, 2.5mol) at room temperature in 2.5 hours slowly
Instill in tetrahydrofuran (7L) solution of ethylenediamine (1200g, 20mol).It is stirred at room temperature 22 hours, after being spin-dried for solvent, adds 5L
Water, is extracted three times with dichloromethane 1.5L, and organic layer merging is washed once with salt, anhydrous sodium sulfate drying, is spin-dried for obtaining 368g oil
Shape thing N- tertbutyloxycarbonyl -1,2- ethylenediamine (yield (based on di-tert-butyl dicarbonate)：92%).
Second step：The synthesis of the chloro- 2- mercaptobenzoxazole of 5-.
By ehtyl potassium xanthate (535.8g, 3.343mol) be slowly added to 2- amino -4- chlorophenol (400g,
In ethanol (3L) solution 2.786mol), and be stirred at room temperature 10 minutes, 80 DEG C are then to slowly warm up to until having reacted
Become.After point plate finds that raw material point disappears, reaction mixture is poured in frozen water (7L) and is neutralized to neutrality with glacial acetic acid.Filter, filter residue
5L frozen water is used successively, 2L n-hexane is washed, drying under reduced pressure obtains the chloro- 2- sulfydryl benzo of white solid (512.5g, 99.1%) 5- and dislikes
Azoles.
3rd step：The synthesis of 2,5- dichloro benzoxazoles.
Thionyl chloride (885g, 7.5mol) and N,N-dimethylformamide (270ml) are added to the chloro- 2- of 5- at 5-10 DEG C
In dichloromethane (5L) solution of mercaptobenzoxazole (540g, 2.903mol).The solution until forming a clarification is stirred, instead
Solution is answered to be stirred at room temperature 4 hours.Reaction terminate after, reactant liquor is poured in 4L frozen water, in 1 hour with sodium acid carbonate slowly in
With to neutral, extracted with dichloromethane (2.5L*2).Organic layer uses salt water washing after merging, sodium sulphate dries, and is spin-dried for obtaining crude product,
The crude product is washed at -20 DEG C with n-hexane (2L*2), filter, be spin-dried for yellow liquid 2,5- dichloro benzoxazoles (496.8g,
91.0%).
4th step：[2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) amino] ethyl] t-butyl carbamate
Synthesis.
(2.5g, 35.7mmol) butenone is slowly added drop-wise to N- tertbutyloxycarbonyl -1,2- ethylenediamine (5.7g, 35.7mmol)
Ether (100ml) solution in, be stirred at room temperature 24 hours.Reactant liquor sequentially adds (6.21ml, 44.6mmol) after being cooled to 0 DEG C
Triethylamine and (6.7g, 35.7mmol) 2,5- dichloro benzoxazoles.Reaction is stirred overnight, after reaction diluted ethyl acetate with according to
Secondary use 10% citric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing.Organic layer anhydrous sodium sulfate drying, filters,
It is spin-dried for obtaining white solid (9.5g, yield 70%).
After testing, the nuclear magnetic spectrogram of white solid is as follows, it may be determined that final product is [the 2- [(chloro- benzoxazoles -2- of 5-
Base) (3- oxo butyl) amino] ethyl] t-butyl carbamate.
NMR(400MHz,CDCl3):δ 7.25 (d, 1H, J=2.2Hz), 7.10 (d, 1H, J-8.4Hz), 6.92 (dd, 1H,
J=8.5,2.2Hz), 5.07 (s, 1H, br), 3.74 (t, 2H, J=6.6Hz), 3.64 (t, 2H, J=6.2Hz), 3.38 (d,
2H, br), 2.90 (t, 2H, J=6.8Hz), 2.15 (s, 3H), 1.34 (s, 9H).
Through measuring and calculating, in the present embodiment, the total recovery of three-step reaction is 55.5%.
Embodiment 2
The first step：The synthesis of N- tertbutyloxycarbonyl -1,2- ethylenediamine.
Chloroform (5L) solution of di-tert-butyl dicarbonate (545g, 2.5mol) was slowly instilled at room temperature in 2.5 hours
In chloroform (7L) solution of ethylenediamine (1200g, 20mol).Be stirred at room temperature 22 hours, 5L water is added after being spin-dried for solvent, use dichloro
Methane 1.5L is extracted three times, and organic layer merging is washed once with salt, and anhydrous sodium sulfate drying is spin-dried for obtaining the tertiary fourth of 376g grease N-
Oxygen carbonyl -1,2- ethylenediamine (yield (based on di-tert-butyl dicarbonate)：94%).
Second step：The synthesis of the chloro- 2- mercaptobenzoxazole of 5-.
By ehtyl potassium xanthate (446.5g, 2.786mol) be slowly added to 2- amino -4- chlorophenol (400g,
In ethanol (3L) solution 2.786mol), and be stirred at room temperature 10 minutes, 80 DEG C are then to slowly warm up to until having reacted
Become.Point plate finds that raw material point does not disappear, and reaction mixture is poured in frozen water (7L) and is neutralized to neutrality with glacial acetic acid.Filter, filter
Slag uses 5L frozen water successively, and 2L n-hexane is washed, and drying under reduced pressure obtains the chloro- 2- sulfydryl benzo of white solid (491.1g, 95%) 5- and dislikes
Azoles.
3rd step：The synthesis of 2,5- dichloro benzoxazoles.
It is chloro- that thionyl chloride (684.4g, 5.8mol) and N,N-dimethylformamide (270ml) are added to 5- at 5-10 DEG C
In dichloromethane (5L) solution of 2- mercaptobenzoxazole (540g, 2.903mol).The solution until forming a clarification is stirred,
Reaction solution is stirred at room temperature 4 hours.After reaction terminates, reactant liquor is poured in 4L frozen water, in 1 hour with sodium acid carbonate slowly
Neutrality is neutralized to, is extracted with dichloromethane (2.5L*2).Organic layer uses salt water washing after merging, sodium sulphate dries, and is spin-dried for slightly
Product, the crude product are washed at -20 DEG C with n-hexane (2L*2), are filtered, are spin-dried for obtaining yellow liquid 2,5- dichloro benzoxazoles
(464g, 85.0%).
4th step：[2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) amino] ethyl] t-butyl carbamate
Synthesis.
(2.25g, 32.13mmol) butenone is slowly added drop-wise to N- tertbutyloxycarbonyl -1,2- ethylenediamine (5.7g,
In ether (100ml) solution 35.7mmol), 24 hours are stirred at room temperature.Reactant liquor sequentially add after being cooled to 0 DEG C (6.21ml,
44.6mmol) triethylamine and (6.7g, 35.7mmol) 2,5- dichloro benzoxazoles.Reaction is stirred overnight, reaction ethyl acetate
Use after dilution and use 10% citric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing successively.Organic layer anhydrous sodium sulfate
Dry, filter, be spin-dried for obtaining white solid (9.2g, yield 68%).
With embodiment 1, detect through nuclear magnetic spectrogram, white solid is defined as [2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxygen
For butyl) amino] ethyl] t-butyl carbamate.
Through measuring and calculating, in the present embodiment, the total recovery of three-step reaction is 51.6%.
Embodiment 3
The first step：The synthesis of N- tertbutyloxycarbonyl -1,2- ethylenediamine.
Dioxane (5L) solution of di-tert-butyl dicarbonate (545g, 2.5mol) at room temperature in 2.5 hours slowly
Instill in dioxane (7L) solution of ethylenediamine (1200g, 20mol).It is stirred at room temperature 22 hours, after being spin-dried for solvent, adds 5L
Water, is extracted three times with dichloromethane 1.5L, and organic layer merging is washed once with salt, anhydrous sodium sulfate drying, is spin-dried for obtaining 390g oil
Shape thing N- tertbutyloxycarbonyl -1,2- ethylenediamine (yield (based on di-tert-butyl dicarbonate)：97%).
Second step：The synthesis of the chloro- 2- mercaptobenzoxazole of 5-.
By ehtyl potassium xanthate (713.3g, 4.45mol) be slowly added to 2- amino -4- chlorophenol (400g,
In ethanol (3L) solution 2.786mol), and be stirred at room temperature 10 minutes, 80 DEG C are then to slowly warm up to until having reacted
Become.After point plate finds that raw material point disappears, reaction mixture is poured in frozen water (7L) and is neutralized to neutrality with glacial acetic acid.Filter, filter residue
5L frozen water is used successively, 2L n-hexane is washed, drying under reduced pressure obtains the chloro- 2- mercaptobenzoxazole of white solid (510g, 98.4%) 5-.
3rd step：The synthesis of 2,5- dichloro benzoxazoles.
Thionyl chloride (1.37kg, 11.6mol) and N,N-dimethylformamide (270ml) are added to 5- at 5-10 DEG C
In dichloromethane (5L) solution of chloro- 2- mercaptobenzoxazole (540g, 2.903mol).Stir until forming the molten of a clarification
Liquid, reaction solution are stirred at room temperature 4 hours.After reaction terminates, reactant liquor is poured in 4L frozen water, uses sodium acid carbonate in 1 hour
Neutrality is slowly neutralized to, is extracted with dichloromethane (2.5L*2).Organic layer uses salt water washing after merging, sodium sulphate dries, and is spin-dried for
Crude product is obtained, the crude product is washed with n-hexane (2L*2) at -20 DEG C, filter, be spin-dried for obtaining yellow liquid 2,5- dichloro benzoxazoles
(469g, 86%).
4th step：[2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) amino] ethyl] t-butyl carbamate
Synthesis.
(2.75g, 39.27mmol) butenone is slowly added drop-wise to N- tertbutyloxycarbonyl -1,2- ethylenediamine (5.7g,
In ether (100ml) solution 35.7mmol), 24 hours are stirred at room temperature.Reactant liquor sequentially add after being cooled to 0 DEG C (6.21ml,
44.6mmol) triethylamine and (6.7g, 35.7mmol) 2,5- dichloro benzoxazoles.Reaction is stirred overnight, reaction ethyl acetate
Use after dilution and use 10% citric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing successively.Organic layer anhydrous sodium sulfate
Dry, filter, be spin-dried for obtaining white solid (9.1g, yield 67%).
With embodiment 1, detect through nuclear magnetic spectrogram, white solid can be identified as [2- [(the chloro- benzoxazoles -2- base of 5-) (3-
Oxo butyl) amino] ethyl] t-butyl carbamate.
Through measuring and calculating, in the present embodiment, the total recovery of three-step reaction is 55%.
It is can be found that by comparing embodiment 1-3：
In embodiment 1,2- amino -4- chlorophenol 3- (4- bromaniline) is 1: 1.2 with the mol ratio of ehtyl potassium xanthate, phase
Higher for 1: 1 reaction yield than mol ratio in 2 second step of embodiment, compare mol ratio in 3 second step of embodiment for 1: 1.6 anti-
Answer yield there is no notable difference, but the usage amount of ehtyl potassium xanthate is reduction of, cost is reduced, therefore, 2- amino -4- chlorine
Phenol 3- (4- bromaniline) and the mol ratio preferably 1: 1.2 of ehtyl potassium xanthate.
In embodiment 1, the mol ratio of the chloro- 2- mercaptobenzoxazole of 5- and thionyl chloride is 1: 2.6, compares embodiment 2 the
In three steps mol ratio for 1: 2 reaction and the 3rd step of embodiment 3 in mol ratio for 1: 4 reaction yield higher, therefore, 5- is chloro-
2- mercaptobenzoxazole and the mol ratio preferably 1: 1.2 of thionyl chloride.
In embodiment 1, N- tertbutyloxycarbonyl -1, the mol ratio of 2- ethylenediamine and butenone is 1: 1, compares embodiment 2 the
In four steps mol ratio for 1: 0.9 reaction with compare mol ratio in the 4th step of embodiment 3 for 1: 1.1 reaction yield higher, because
This, N- tertbutyloxycarbonyl -1, the mol ratio preferably 1: 1 of 2- ethylenediamine and butenone.
Comparative example
The synthetic route of this comparative example is as follows：
The first step：The synthesis of the chloro- 2- mercaptobenzoxazole of 5-.
By ehtyl potassium xanthate (893.2g, 5.572mol) be slowly added to 2- amino -4- chlorophenol (400g,
In ethanol (3L) solution 2.786mol), and be stirred at room temperature 10 minutes, 80 DEG C are then to slowly warm up to until having reacted
Become.After point plate finds that raw material point disappears, reaction mixture is poured in frozen water (7L) and is neutralized to neutrality with glacial acetic acid (752ml).Cross
5L frozen water is used in filter, filter residue successively, and 2L n-hexane is washed, and drying under reduced pressure obtains the chloro- 2- sulfydryl benzene of white solid (510g, 98.4%) 5-
And oxazole.
Second step：The synthesis of 2,5- dichloro benzoxazoles.
Thionyl chloride (540ml) and N,N-dimethylformamide (270ml) are added to the chloro- 2- sulfydryl benzene of 5- at 5-10 DEG C
And in dichloromethane (5L) solution of oxazole (540g, 2.903mol).Stir the solution until forming a clarification, reaction solution
It is stirred at room temperature 4 hours.After reaction terminates, reactant liquor is poured in 4L frozen water, in 1 hour with sodium acid carbonate (1440g) slowly
Neutrality is neutralized to, is extracted with dichloromethane (2.5L*2).Organic layer uses salt water washing after merging, sodium sulphate (300g) dries, rotation
Do crude product is obtained, the crude product is washed with n-hexane (2L*2) at -20 DEG C, filter, be spin-dried for obtaining yellow liquid 2,5- dichloro benzo evil
Azoles (475g, 88.9%).
3rd step：The synthesis of N- [2- [(the chloro- 2- benzoxazolyl of 5-) amino] ethyl] t-butyl carbamate.
Triethylamine (536ml, 3.852mol) and N- tertbutyloxycarbonyl -1,2- ethylenediamine (487ml, 3.081mol) are dissolved in
In 500ml dichloromethane, the solution be slowly added within half an hour at 5-10 DEG C 2,5- dichloro benzoxazoles (470g,
In dichloromethane (400ml) solution 2.568mol).Reactant liquor adds 10L water and uses dichloro after being stirred at room temperature 16 hours
Methane (2*1.5L) is extracted, and is merged organic layer and is used salt water washing, and anhydrous sodium sulfate drying is filtered and is spin-dried for obtaining crude product.The crude product
It is beaten with 1.5L n-hexane and 500ml methyl tertiary butyl ether(MTBE), filters, be spin-dried for, [[(5- is chloro- for 2- for dry a white solid N-
2- benzoxazolyl) amino] ethyl] t-butyl carbamate (666g, 85.3%).
4th step：[2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) amino] ethyl] t-butyl carbamate
Synthesis.
Butenone (528ml, 6.346mol) and 1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene (632ml,
4.230mol) be added at 0-5 DEG C N- [2- [(the chloro- 2- benzoxazolyl of 5-) amino] ethyl] t-butyl carbamate (660g,
In DMF (6L) solution 2.115mol), then stir 16 hours under room temperature.Reactant liquor pours 10L frozen water into
In and with ethyl acetate (7L) extract.Organic layer water (2L) is washed twice, is dry, is spin-dried for obtaining crude product.Crude product n-hexane
(1.5L) it is beaten with methyl tertiary butyl ether(MTBE) (500ml), filters, drying under reduced pressure obtains a white solid (386g, 47.7%).
Detect through nuclear magnetic spectrogram, white solid can be identified as [2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) ammonia
Base] ethyl] t-butyl carbamate.
Through measuring and calculating, in this comparative example, the total recovery of four-step reaction is 35.6%.
Claims (5)
1. a kind of preparation of [2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) amino] ethyl] t-butyl carbamate
Method, comprises the steps：
1) chloroform of di-tert-butyl dicarbonate, dioxane or tetrahydrofuran solution are instilled the corresponding molten of ethylenediamine at room temperature
In the solution of agent, stir and terminate to reaction, water is added after being spin-dried for solvent, extracted with dichloromethane, organic layer merging saline solution
Wash, dry, be spin-dried for obtaining N- tertbutyloxycarbonyl -1,2- ethylenediamine；
2) ehtyl potassium xanthate is added in the ethanol solution of 2- amino -4- chlorophenol, and is stirred at room temperature, then slowly
Heating up and completing until reaction, reaction mixture is poured in frozen water and neutrality is neutralized to acid；Filter, filter residue successively with frozen water, just oneself
Alkane is washed, and drying under reduced pressure obtains the chloro- 2- mercaptobenzoxazole of 5-；
3) thionyl chloride and N,N-dimethylformamide are added to the dichloromethane of the chloro- 2- mercaptobenzoxazole of 5- at 5-10 DEG C
In solution；After reaction solution is stirred at room temperature until reaction terminates, reactant liquor is poured in frozen water, in being neutralized to sodium acid carbonate
Property, extracted with dichloromethane；Organic layer uses brine It after merging, and sodium sulphate dries, and is spin-dried for obtaining crude product, the crude product with just oneself
Alkane is washed, and is filtered, is spin-dried for obtaining 2,5- dichloro benzoxazoles；
4) butenone is added drop-wise to N- tertbutyloxycarbonyl -1, in the diethyl ether solution of 2- ethylenediamine, stirring；After reactant liquor is cooled to 0 DEG C,
Triethylamine and 2,5- dichloro benzoxazoles is sequentially added, is stirred and completes until reaction, after product diluted ethyl acetate, according to
Secondary use 10% citric acid, saturated sodium bicarbonate aqueous solution and saturated common salt water washing；Organic layer anhydrous sodium sulfate drying, mistake
Filter, is spin-dried for [2- [(the chloro- benzoxazoles -2- base of 5-) (3- oxo butyl) amino] ethyl] t-butyl carbamate；
Step 2) in, 2- amino -4- chlorophenol 3- (4- bromaniline) is 1: 1～1.6 with the mol ratio of ehtyl potassium xanthate；
Step 3) in, the chloro- 2- mercaptobenzoxazole of 5- is 1: 2～4 with the mol ratio of thionyl chloride；
Step 4) in, N- tertbutyloxycarbonyl -1,2- ethylenediamine are 1: 0.9～1.1 with the mol ratio of butenone.
2. preparation method as claimed in claim 1, it is characterised in that step 2) in, 2- amino -4- chlorophenol 3- (4- bromobenzene
Amine) it is 1: 1.2 with the mol ratio of ehtyl potassium xanthate.
3. preparation method as claimed in claim 1, it is characterised in that step 3) in, the chloro- 2- mercaptobenzoxazole of 5- and chlorination
The mol ratio of sulfoxide is 1: 2.6.
4. preparation method as claimed in claim 1, it is characterised in that step 4) in, N- tertbutyloxycarbonyl -1,2- ethylenediamine with
The mol ratio of butenone is 1: 1.
5. preparation method as claimed in claim 1, it is characterised in that step 2) in, for the acid of neutralization reaction mixed liquor it is
Hydrochloric acid, glacial acetic acid, sulfuric acid, formic acid, trifluoroacetic acid or oxalic acid.
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| CN113929673A (en) * | 2021-09-03 | 2022-01-14 | 湖南华腾医药有限公司 | Continuous flow micro-reaction synthesis method of suvorexant intermediate |
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| WO2012148533A1 (en) * | 2011-04-28 | 2012-11-01 | Isp Investments Inc. | Lactamic polymers containing an acetoacetate moiety |
| 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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| WO2012148533A1 (en) * | 2011-04-28 | 2012-11-01 | Isp Investments Inc. | Lactamic polymers containing an acetoacetate moiety |
| 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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| CARL A. BAXTER ET AL.: "The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder", 《ORG. PROCESS RES. DEV》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113929673A (en) * | 2021-09-03 | 2022-01-14 | 湖南华腾医药有限公司 | Continuous flow micro-reaction synthesis method of suvorexant intermediate |
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