CN106316967A - Selexipag intermediates and method for preparing selexipag - Google Patents
Selexipag intermediates and method for preparing selexipag Download PDFInfo
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- CN106316967A CN106316967A CN201610697954.1A CN201610697954A CN106316967A CN 106316967 A CN106316967 A CN 106316967A CN 201610697954 A CN201610697954 A CN 201610697954A CN 106316967 A CN106316967 A CN 106316967A
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- 0 *CCCCOC1OCCCC1 Chemical compound *CCCCOC1OCCCC1 0.000 description 1
- HITLIUPMOWUKAX-UHFFFAOYSA-N CC(C)Nc1nc(-c2ccccc2)c(-c2ccccc2)nc1 Chemical compound CC(C)Nc1nc(-c2ccccc2)c(-c2ccccc2)nc1 HITLIUPMOWUKAX-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
- C07D241/20—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/52—Y being a hetero atom
- C07C311/53—X and Y not being nitrogen atoms, e.g. N-sulfonylcarbamic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
- C07D309/10—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to the field of chemical preparation, and relates to selexipag intermediates and a method for preparing selexipag. The selexipag intermediates are a compound SLP-4, a compound SLP-7, a compound SLP-8 and a compound SLP-10. The selexipag intermediates and the method have the advantages that the method for preparing the selexipag includes reasonable routes and is low in cost and operative difficulty and little in environmental pollution, raw materials are easily available, accordingly, requirements of large-scale industrial production can be met by the method, and the like.
Description
Technical field
The invention belongs to chemical preparation techniques field, be specifically related to a kind of West handkerchief lattice intermediate and the preparation of West handkerchief lattice
Method.
Background technology
Pulmonary hypertension is a kind of chronic progressive external pulmonary disease, and prognosis is the best, and patient may premature death or need lung
Transplant.West handkerchief lattice are a kind of oral Ip prostacyclin receptor stimulating agents, and can relax vascular smooth muscle, expand blood vessel,
Reduce pulmonary artery pressure.In December, 2015, U.S. FDA ratifies recruit's entity medicine of Ai Kelong (Actelion) company exploitation
West handkerchief lattice (Selexipag, CAS:475086-01-2, trade name Uptravi) list, for adult pulmonary high pressure patient
Treatment.Its chemical constitution is as shown in formula SLP-11:
Patent US7205302B2, it is provided that the syntheti c route of Yuan Yan company, as follows:
First, starting material 4-aminobutanol (formula R1-1) under platinum oxide is catalyzed, carries out high pressure reduction condensation at acetone
Obtain 4-isopropyl aminobutanol (formula R1-2).Then, 4-isopropyl aminobutanol (formula R1-2) and 2-chloro-5,6-diphenyl piperazine
190 degree of pyrocondensations of piperazine (formula SLP-3), obtain intermediate (formula SLP-9).Finally, intermediate SLP-9 and bromo-acetic acid tert-butyl contracting
Close, tert-butyl ester base is sloughed in hydrolysis and methylsulfonamides is condensed to yield West handkerchief lattice (formula SLP-11).
The totally 5 step reaction of whole piece syntheti c route.First step high-pressure hydrogenation, industrialization needs special installation, risk higher.Second
Step pyrocondensation, industrialization needs special installation；And need intermediate 4-isopropyl aminobutanol (formula R1-2) self conduct
Reaction dissolvent and significantly excess, with high costs；Simultaneously because 2-chloro-5,6-diphenyl piperazine (formula SLP-3) reactivity is relatively low,
This step yield is the highest.And intermediate R1-4 and R1-5 of follow-up several step, human facial skin is had stronger zest, easily makes
Become operator face red and swollen and pruritus；Simultaneously because intermediate SLP-9 has formed main mother nucleus structure, several main costlinesses
Fragment have been incorporated into molecular structure, then through three-step reaction, connect the small fragment that remaining two prices are less expensive, follow-up
Three-step reaction yield is relatively low so that the expensive fragment introducing molecule in advance is lost in vain, and whole synthetic route is with high costs.So
Generally speaking, the syntheti c route that patent US7205302B2 provides has obviously defect, and production cost is the highest, reaction behaviour
Make difficulty big, safety is also unfavorable for large-scale industrial production.
Summary of the invention
It is an object of the invention to the defect for existing process route, it is provided that West handkerchief lattice intermediate and West handkerchief lattice
Preparation method.Use process route and the method for the present invention, raw material that is cheap and that be easy to get can be used, significantly improve conjunction
Become yield, so that the production cost of West handkerchief lattice is greatly reduced；Greatly reduce the operation easier of synthetic reaction simultaneously
And risk, it is easy to industrialization is amplified.
It is an object of the invention to be achieved through the following technical solutions:
First aspect, the present invention relates to a kind of West handkerchief lattice intermediate A, and structural formula is shown below:
Second aspect, the present invention relates to the preparation method of a kind of West handkerchief lattice intermediate A, comprises the steps:
The compound with structure shown in formula SLP-3 reacts with 2-aminopropane., obtains the West with structure shown in formula SLP-4
Handkerchief lattice intermediate A；
Preferably, described reaction is carried out under organic solvent and/or organic base existence condition.
It is highly preferred that described organic solvent is at least one in toluene, dimethylbenzene, chlorobenzene；Described organic base is pyrrole
Pyridine, 2, at least one in 6-lutidines, 2，4，6-trimethylpyridine, triethylamine.
The third aspect, the present invention relates to a kind of West handkerchief lattice intermediate B, and structural formula is shown below:
Wherein, X is chlorine, bromine or iodine.
Fourth aspect, the present invention relates to the preparation method of a kind of West handkerchief lattice intermediate B, comprises the steps:
Step 1, has the compound and 3 of structure shown in formula SLP-5, and 4-dihydropyran reacts, and obtains having formula SLP-6 institute
Show the compound of structure；
Step 2, the compound with structure shown in formula SLP-6 reacts with halogen and triphenylphosphine, obtains having formula SLP-7
The West handkerchief lattice intermediate B of shown structure；Described halogen is chlorine, bromine or iodine；
Wherein, X is chlorine, bromine or iodine.
Preferably, the reaction of described step 1 is carried out under organic solvent and alkali existence condition；Described organic solvent is dichloro
At least one in methane, chloroform, oxolane；Described alkali be pyridine, triethylamine, 2,6-lutidines and 2,4,
At least one in 6-trimethylpyridine.
Preferably, the reaction of described step 2 is carried out under organic solvent existence condition；Described organic solvent is dichloromethane
Alkane, 1, at least one in 2-dichloroethanes, chloroform, glycol dibromide.
5th aspect, the present invention relates to a kind of West handkerchief lattice intermediate A B, and structural formula is shown below:
6th aspect, the present invention relates to the preparation method of a kind of West handkerchief lattice intermediate A B, comprises the steps:
West handkerchief lattice intermediate A is reacted with West handkerchief lattice intermediate B, obtains the West handkerchief with structure shown in formula SLP-8
Lattice intermediate A B；
Wherein, X is chlorine, bromine or iodine.
Preferably, described West handkerchief lattice intermediate A is reacted with West handkerchief lattice intermediate B and be there is bar at highly basic and organic solvent
Carry out under part；Described highly basic is Feldalat NM, Sodium ethylate, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, hexamethyl two silicon
At least one in alkylamino lithium, hexamethyldisilane Sodamide., sodium hydride.
It is highly preferred that described highly basic is sodium hydride or potassium tert-butoxide.
7th aspect, the present invention relates to a kind of West handkerchief lattice intermediate C, and structural formula is shown below:
Wherein, X is chlorine or bromine.
Eighth aspect, the present invention relates to the preparation method of a kind of West handkerchief lattice intermediate C, comprises the steps:
In organic solvent, and methylsulfonamides reaction obtains the West handkerchief with structure shown in formula SLP-10 to halogen acyl halide
Lattice intermediate C；In described halogen acyl halide, halogen is chlorine or bromine；
Wherein, X is chlorine or bromine.
Preferably, described organic solvent is oxolane, methyl tertiary butyl ether(MTBE), ethyl acetate, butyl acetate, the tertiary fourth of acetic acid
At least one in ester, dimethyl sulfoxide, DMF.
It is highly preferred that described organic solvent is ethyl acetate.
9th aspect, the present invention relates to the preparation method of a kind of West handkerchief lattice, comprises the steps:
Step 1, West handkerchief lattice intermediate A B and acid reaction obtain the compound with structure shown in formula SLP-9；
Step 2, has the compound of structure shown in formula SLP-9, in the presence of highly basic, in organic solvent with West handkerchief lattice
Intermediate C reacts, and obtains the West handkerchief lattice with structure shown in formula SLP-11；
Wherein, X is chlorine or bromine.
Preferably, in step 1, described acid is formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulphuric acid, nitric acid, to methylbenzene sulphur
The mixing of one or more in acid.
Preferably, in step 1, described reaction is carried out under organic solvent existence condition；Described solvent be alcohol, ester,
The mixing of one or more in ether, dimethyl sulfoxide, DMF.
Preferably, in step 2, described reaction is carried out under organic solvent and highly basic existence condition；Described is organic molten
Agent is oxolane, dichloromethane, chloroform, DMF, dimethyl sulfoxide, in N-Methyl pyrrolidone
The mixing of one or more；Described highly basic is Feldalat NM, Sodium ethylate, potassium tert-butoxide, sodium tert-butoxide, n-BuLi, diisopropyl
One or several mixing in base Lithamide., hexamethyldisilane Lithamide., hexamethyldisilane Sodamide., sodium hydride.
It is further preferred that in step 1, described solvent is ethyl acetate, methanol；Described acid is hydrochloric acid, to toluene sulphur
Acid；
In step 2, described solvent is N-Methyl pyrrolidone, DMF；Described alkali is the tert-butyl alcohol
Potassium, sodium hydride.
In the present invention, described structural formula compound as shown in formula SLP-3 can be according in patent US7205302B2
Method synthesis obtains, and the synthesis of this raw material belongs to the general knowledge of this area, and those skilled in the art can also be by disclosed commercially available
Channel obtains.
Compared with prior art, the present invention has a following beneficial effect:
1) present invention devises a new synthetic route and prepares the West handkerchief lattice with structure shown in formula SLP-11, and
It is achieved；
2) preparation method that the present invention provides, has the advantage that reaction yield is high, source chemicals is easy to get, significantly reduces west
The production cost of Li Page；
3) preparation method that the present invention provides, has that operation easier is low, production risk is low a little, the most extensive work
The realization that industry metaplasia is produced.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in detail.Following example will assist in the technology of this area
Personnel are further appreciated by the present invention, but limit the present invention the most in any form.It should be pointed out that, the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, it is also possible to make some deformation and improvement.These broadly fall into the present invention
Protection domain.
The present invention prepares the synthetic route of West handkerchief lattice (Selexipag, CAS:475086-01-2):
Embodiment 1, the preparation of SLP-4
In 10 liters of reactors, add 2 liters of 2-aminopropane .s and add 222 grams of SLP-3, being stirred at room temperature and react 48 hours to reacting knot
Bundle.
Add 5 liters of ethyl acetate and the stirring of 3 liters of water, stand split-phase；Organic facies is successively with dilute hydrochloric acid, water, unsaturated carbonate hydrogen
Sodium washs, and anhydrous sodium sulfate is dried, filters, concentrates, obtains crude product；Crude product recrystallization from ethyl acetate/petroleum ether, obtains 205
Gram white solid SLP-4.Yield: 85%.
1H NMR (400MHz, CDCl3): δ 7.89 (s, 1H), 7.43-7.22 (m, 10H), 4.59 (d, 1H), 4.08 (m,
1H), 1.30 (d, 6H)
ESI/MS+(m/z):289
Embodiment 2, the preparation of SLP-6
In 10 liters of reactors, add 0.36 kilogram of BDO (formula SLP-5), 70 grams of p-methyl benzenesulfonic acid and 3 liters of dichloros
In methane, stirring and dissolving；It is slowly added 0.35 kilogram 3,4-dihydropyran, reaction overnight extremely reaction is stirred at room temperature and terminates.
Add 3 liters of water, stir, stand split-phase；Organic facies anhydrous sodium sulfate is dried, filters, concentrates, and obtains 640 grams of nothings
Color grease SLP-6.Yield: 92%.
1H NMR (400MHz, CDCl3): δ 4.59 (m, 1H), 3.93-3.78 (m, 2H), 3.63-3.55 (m, 2H),
3.52-3.40 (m, 2H), 2.68 (s, 1H), 1.83-1.50 (m, 10H)
ESI/MS+(m/z):174
Embodiment 3, the preparation of SLP-7a
In 10 liters of reactors, adding 640 grams of SLP-6,5 liters of toluene, 1.0 kilograms of triphenylphosphines and 320 grams of imidazoles, stirring is extremely
Dissolve completely；Under nitrogen protection, after being cooled to 0 degree, it is dividedly in some parts 910 grams of iodines, controls reaction temperature less than 10 degree；
After adding completely, it is warmed to room temperature reaction and terminates to reaction for 3 hours.
Add 3 liters of water, stir, stand split-phase.Organic facies anhydrous sodium sulfate is dried, filters, concentrates, and obtains crude product；Slightly
Product ethyl acetate/petroleum ether system column chromatography is purified, and obtains 780 grams of faint yellow oily SLP-7a (X=I).Yield: 76%.
H NMR (400MHz, CDCl3): δ 4.58 (m, 1H), 3.93-3.78 (m, 2H), 3.52-3.40 (m, 2H), 3.22
(t, 2H), 1.93-1.50 (m, 10H)
ESI/MS+(m/z):284
Embodiment 4, the preparation of SLP-7b
In 10 liters of reactors, adding 640 grams of SLP-6,5 liters of toluene, 1.0 kilograms of triphenylphosphines and 320 grams of imidazoles, stirring is extremely
Dissolve completely；Under nitrogen protection, after being cooled to 0 degree, it is dividedly in some parts 570 grams of bromines, controls reaction temperature less than 10 degree；Add
After entering completely, it is warmed to room temperature reaction and terminates to reaction for 3 hours.
Add 3 liters of water, stir, stand split-phase.Organic facies anhydrous sodium sulfate is dried, filters, concentrates, and obtains crude product；Slightly
Product ethyl acetate/petroleum ether system column chromatography is purified, and obtains 697 grams of faint yellow oily SLP-7b (X=Br).Yield: 80%.
H NMR (400MHz, CDCl3): δ 4.57 (m, 1H), 3.93-3.78 (m, 2H), 3.52-3.40 (m, 2H), 3.22
(t, 2H), 1.93-1.50 (m, 10H)
ESI/MS+(m/z):237
Embodiment 5, the preparation of SLP-7c
In 10 liters of reactors, adding 640 grams of SLP-6,5 liters of toluene, 1.0 kilograms of triphenylphosphines and 320 grams of imidazoles, stirring is extremely
Dissolve completely；Under nitrogen protection, after being cooled to 0 degree, it is slowly introducing 300 grams of chlorine, controls reaction temperature less than 10 degree；Add
After entering completely, it is warmed to room temperature reaction and terminates to reaction for 3 hours.
Add 3 liters of water, stir, stand split-phase.Organic facies anhydrous sodium sulfate is dried, filters, concentrates, and obtains crude product；Slightly
Product ethyl acetate/petroleum ether system column chromatography is purified, and obtains 550 grams of faint yellow oily SLP-7b (X=Cl).Yield: 78%.
H NMR (400MHz, CDCl3): δ 4.55 (m, 1H), 3.95-3.79 (m, 2H), 3.52-3.40 (m, 2H), 3.23
(t, 2H), 1.93-1.52 (m, 10H)
ESI/MS+(m/z):193
Embodiment 6, the preparation of SLP-8:
In 10 liters of reactors, add 205 grams of SLP-4 and 2 liters of DMF, after stirring and dissolving is complete, be cooled to 0 DEG C；It is dividedly in some parts
60 grams of sodium hydrides, stir 30 points at low temperature 0 DEG C；Add and be dividedly in some parts 390 grams of SLP-7a, control temperature and be not more than 5 DEG C；Add
Quan Hou, is gradually increased to 25 DEG C of reactions and terminates to reaction for 24 hours.
It is slowly added dropwise into 0.5 liter of dehydrated alcohol cancellation reaction, adds 4 liters of ethyl acetate and 3 liters of water, stir, stand split-phase；
Organic phases washed with water, anhydrous sodium sulfate are dried, filter, concentrate, and obtain 252 grams of yellow solid SLP-8.Yield: 81%.
Embodiment 7, the preparation of SLP-8:
In 10 liters of reactors, add 205 grams of SLP-4 and 2 liters of DMF, after stirring and dissolving is complete, be cooled to 0 DEG C；It is dividedly in some parts
60 grams of sodium hydrides, stir 30 points at low temperature 0 DEG C；Add and be dividedly in some parts 340 grams of SLP-7b, control temperature and be not more than 5 DEG C；Add
Quan Hou, is gradually increased to 25 DEG C of reactions and terminates to reaction for 24 hours.
It is slowly added dropwise into 0.5 liter of dehydrated alcohol cancellation reaction, adds 4 liters of ethyl acetate and 3 liters of water, stir, stand split-phase；
Organic phases washed with water, anhydrous sodium sulfate are dried, filter, concentrate, and obtain 265 grams of yellow solid SLP-8.Yield: 85%.
Embodiment 8, the preparation of SLP-8:
In 10 liters of reactors, add 205 grams of SLP-4 and 2 liters of DMF, after stirring and dissolving is complete, be cooled to 0 DEG C；It is dividedly in some parts
60 grams of sodium hydrides, stir 30 points at low temperature 0 DEG C；Add and be dividedly in some parts 275 grams of SLP-7c, control temperature and be not more than 5 DEG C；Add
Quan Hou, is gradually increased to 25 DEG C of reactions and terminates to reaction for 24 hours.
It is slowly added dropwise into 0.5 liter of dehydrated alcohol cancellation reaction, adds 4 liters of ethyl acetate and 3 liters of water, stir, stand split-phase；
Organic phases washed with water, anhydrous sodium sulfate are dried, filter, concentrate, and obtain 274 grams of yellow solid SLP-8.Yield: 88%.
Embodiment 9, the preparation of SLP-9:
In 10 liters of reactors, add 252 grams of SLP-8,50 grams of p-methyl benzenesulfonic acids and 5 liters of ethyl acetate, be stirred at room temperature anti-
Answer 12 hours and terminate to reaction.
Add 2 liters of water, stir, stand split-phase.Organic facies anhydrous sodium sulfate is dried, filters, concentrates, and obtains crude product；Slightly
Product recrystallization from ethyl acetate/petroleum ether, obtains 192 grams of faint yellow solid SLP-9.Yield: 95%.
H NMR (400MHz, CDCl3): δ 8.05 (s, 1H), 7.42-7.20 (m, 10H), 4.72 (m, 1H), 3.72 (t,
2H), 3.42 (t, 2H), 1.73-1.50 (m, 4H), 1.26 (d, 6H)
ESI/MS+(m/z):361
Embodiment 10, the preparation of SLP-10a:
In 2 liters of reaction bulbs, add 1 liter of ethyl acetate and 66 grams of methylsulfonamides, be slowly added into 140 grams of bromoacetyl bromides；By
Edge up to 65 DEG C of reactions extremely to react for 12 hours and terminate.
Reactant liquor is gradually cooled to 0 degree, and a large amount of white solids separate out；Filtering drying, obtains 138 white grams of solid SLP-10a
(X=Br).Yield: 92%.
H NMR (400MHz, CDCl3): δ 4.04 (s, 2H), 3.26 (s, 3H)
ESI/MS+(m/z):214
Embodiment 11, the preparation of SLP-10b:
In 2 liters of reaction bulbs, add 1 liter of ethyl acetate and 66 grams of methylsulfonamides, be slowly added into 109 grams of chloracetyl chlorides；By
Edge up to 65 DEG C of reactions extremely to react for 12 hours and terminate.
Reactant liquor is gradually cooled to 0 degree, and a large amount of white solids separate out；Filtering drying, obtains 112 white grams of solid SLP-10b
(X=Cl).Yield: 94%.
H NMR (400MHz, CDCl3): δ 4.02 (s, 2H), 3.28s, 3H)
ESI/MS+(m/z):171
Embodiment 12, the preparation of SLP-11 (West handkerchief lattice):
In 10 liters of reactors, 192 grams of SLP-9 are dissolved in 2 liters of N-Methyl pyrrolidone；It is slowly added into 67 grams of potassium tert-butoxides
After, then it is dividedly in some parts 138 grams of SLP-10a (0.69mol)；It is stirred at room temperature 12 hours and terminates to reaction.
Slow cooling, to 0 DEG C, adds 2 kilograms of frozen water and adds the ethyl acetate washing of 3 liters, stirring, stand split-phase；Organic
It is dried with anhydrous sodium sulfate, filters, concentrates, obtain crude product；Crude product with ethyl acetate/petroleum ether crystallize, dense obtain 212 grams light
Yellow solid SLP-11 (West handkerchief lattice).Yield: 81%, purity 99.5%.
H NMR (400MHz, CDCl3): δ 8.04 (s, 1H), 7.42-7.20 (m, 10H), 4.73 (m, 1H), 3.62 (t,
2H), 3.47 (t, 2H), 3.29 (s, 3H), 1.73-1.50 (m, 4H), 1.24 (d, 6H)
ESI/MS+(m/z):496
Embodiment 13, the preparation of SLP-11 (West handkerchief lattice):
In 10 liters of reactors, 192 grams of SLP-9 are dissolved in 2 liters of N-Methyl pyrrolidone；It is slowly added into 67 grams of potassium tert-butoxides
After, then it is dividedly in some parts 112 grams of SLP-10b (0.7mol)；It is stirred at room temperature 12 hours and terminates to reaction.
Slow cooling, to 0 DEG C, adds 2 kilograms of frozen water and adds the ethyl acetate washing of 3 liters, stirring, stand split-phase；Organic
It is dried with anhydrous sodium sulfate, filters, concentrates, obtain crude product；Crude product with ethyl acetate/petroleum ether crystallize, dense obtain 219 grams light
Yellow solid SLP-11 (West handkerchief lattice).Yield: 83%, purity 99.2%.
In sum, the present invention devise a new synthetic route to prepare West handkerchief lattice (Selexipag, CAS:
475086-01-2), and be achieved；This synthetic route has good reaction selectivity yield height, the gentle operation easier of reaction
The advantages such as low, raw material is easy to get, are very beneficial for the realization of industrialized production；The cost of material that this synthetic route uses simultaneously is low
The feature that honest and clean, totle drilling cost is low, is beneficial to promote the large-scale commercial application of West handkerchief lattice product.
The concrete application approach of the present invention is a lot, and the above is only the preferred embodiment of the present invention.It should be pointed out that, above
Embodiment is merely to illustrate the present invention, and is not limited to protection scope of the present invention.Common skill for the art
For art personnel, under the premise without departing from the principles of the invention, it is also possible to make some improvement, these improvement also should be regarded as this
Bright protection domain.
Claims (10)
1. a West handkerchief lattice intermediate A, it is characterised in that structural formula is shown below:
2. the preparation method of a West as claimed in claim 1 handkerchief lattice intermediate A, it is characterised in that comprise the steps:
The compound with structure shown in formula SLP-3 reacts with 2-aminopropane., obtains the West handkerchief lattice with structure shown in formula SLP-4
Intermediate A；
3. a West handkerchief lattice intermediate B, it is characterised in that structural formula is shown below:
Wherein, X is chlorine, bromine or iodine.
4. the preparation method of a West as claimed in claim 3 handkerchief lattice intermediate B, it is characterised in that comprise the steps:
Step 1, has the compound and 3 of structure shown in formula SLP-5, and 4-dihydropyran reacts, and obtains having knot shown in formula SLP-6
The compound of structure；
Step 2, the compound with structure shown in formula SLP-6 reacts with halogen and triphenylphosphine, obtains having shown in formula SLP-7
The West handkerchief lattice intermediate B of structure；Described halogen is chlorine, bromine or iodine；
Wherein, X is chlorine, bromine or iodine.
5. West handkerchief lattice intermediate A B, it is characterised in that structural formula is shown below:
6. the preparation method of West as claimed in claim 5 handkerchief lattice intermediate A B, it is characterised in that include walking as follows
Rapid:
West handkerchief lattice intermediate A is reacted with West handkerchief lattice intermediate B, obtains having in the West handkerchief lattice of structure shown in formula SLP-8
Mesosome AB；
Wherein, X is chlorine, bromine or iodine.
7. a West handkerchief lattice intermediate C, it is characterised in that structural formula is shown below:
Wherein, X is chlorine or bromine.
8. the preparation method of a West handkerchief lattice intermediate C as claimed in claim 7, it is characterised in that comprise the steps:
In organic solvent, and methylsulfonamides reaction obtains having in the West handkerchief lattice of structure shown in formula SLP-10 halogen acyl halide
Mesosome C；In described halogen acyl halide, halogen is chlorine or bromine；
Wherein, X is chlorine or bromine.
9. the preparation method of West handkerchief lattice, it is characterised in that comprise the steps:
Step 1, West handkerchief lattice intermediate A B and acid reaction obtain the compound with structure shown in formula SLP-9；
Step 2, has the compound of structure shown in formula SLP-9, in the presence of highly basic, in organic solvent with West handkerchief lattice in the middle of
Body C reacts, and obtains the West handkerchief lattice with structure shown in formula SLP-11；
Wherein, X is chlorine or bromine.
10. the preparation method of West as claimed in claim 9 handkerchief lattice, it is characterised in that in step 1, described acid is formic acid,
The mixing of one or more in acetic acid, trifluoroacetic acid, hydrochloric acid, sulphuric acid, nitric acid, p-methyl benzenesulfonic acid.
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