CN105949135A - Synthetic method of selexipag - Google Patents
Synthetic method of selexipag Download PDFInfo
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- CN105949135A CN105949135A CN201610303627.3A CN201610303627A CN105949135A CN 105949135 A CN105949135 A CN 105949135A CN 201610303627 A CN201610303627 A CN 201610303627A CN 105949135 A CN105949135 A CN 105949135A
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- 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
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Abstract
The invention discloses a synthetic method of selexipag. According to the method, 4-[(t-butyloxycarboryl)(isopropyl) amino]-1-butanol and tert-butyl bromoacetate are subjected to a condensation reaction, and obtained 4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl] tert-butyl acetate is subjected to a hydrolysis reaction under an alkaline reaction; obtained 4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl] acetic acid and methanesulfonamide are subjected to a condensation reaction; obtained 2-[4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl]-N-(methylsulfonyl) acetamide is subjected to a deprotection reaction under an acid condition, obtained 2-[4-(isopropyl) amino butoxyl]-N-(methylsulfonyl) acetamide and 5-chloro-2,3-diphenyl pyrazine are subjected to a substitution reaction, and the finished product selexipag is obtained. The method has a reasonable and concise process route and is environment-friendly and suitable for industrial production, the operation is simplified, and the cost is relatively low.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to a kind of new drug Sai Lexipa for treating pulmonary hypertension
Synthetic method.
Background technology
The chemistry entitled 2-[4-(5,6-of selectivity non-prostanoid IP prostacyclin receptor agonist Sai Lexipa (Selexipag)
Diphenyl pyrazine-2-base) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, its chemical structural formula is:
Sai Lexipa is pulmonary hypertension (PAH) the treatment new drug of Actelion biopharmaceutical company of Switzerland research and development, in 2015
Obtain FDA approval the end of the year, and just start the additive treatment after Primary Care as patients with pulmonary hypertension and promote, it is contemplated that list first year energy
Enough realizing the income from sales of 200,000,000 dollars, 2020 sales forecasts reach more than 600,000,000 dollars.Pulmonary hypertension be a kind of chronic,
The pulmonary disease progressively deteriorated, is characterized in that abnormal hypertension occurs in pulmonary artery, patient's daily routines can be caused tired out.Due to the heart
Blood is transported to pulmonary by the influential point of viscera more hardy, and this disease can frequently result in fatefulue heart failure, and patient may premature death
Or need lung transplantation.The Ip prostacyclin receptor agonism agent medicine that Sai Lexipa is administered orally as a kind of selectivity, with other with ring
Prostaglandin path is target spot, must suck or the medicine of intravenous administration is compared, and the most convenient, can relax blood
Tube wall smooth muscle, expands blood vessel, reduces pulmonary artery pressure.
Patent WO2011017612, document " Journal ofMedicinal Chemistry 2015, Vol.58, p.7128-7137. " and
" p.6692-6704. " Bioorganic and Medicinal Chemistry 2007, Vol.15 reports and a kind of prepares Sai Lexipa's
Synthetic route, its process route is as follows:
This synthetic route is raw material with 5-chloro-2,3-diphenyl pyrazine and 4-(isopropylamino)-n-butyl alcohol, by replacement, coupling,
The multistep reactions such as condensation, make the continuous superposition of functional group, prepare target product Sai Lexipa.Due to 4-(isopropylamino)-n-butyl alcohol
As raw material, its structure has-NH and-OH group so that the substitution reaction of the first step produces the competitive secondary anti-of diverse location
Should, introduce impurity, intermediate down and the quality of product and purifying process are all adversely affected, cause operation complicated numerous
Trivial, it is unfavorable for amplifying and produces and Industry Promotion, it is therefore necessary to explore that technological process is short, simple to operate, with low cost and mat
Synthetic method with the Sai Lexipa of applicable industrialized production.
Summary of the invention
For the deficiencies in the prior art and defect, it is an object of the invention to provide the synthetic method of a kind of Sai Lexipa.
In order to realize foregoing invention purpose, the technical solution used in the present invention is:
The synthetic route of described Sai Lexipa is
Specifically comprising the following steps that of the synthetic method of Sai Lexipa
(1) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared: by 4-[(tertbutyloxycarbonyl) (isopropyl)
Amino]-n-butyl alcohol and bromo-acetic acid tert-butyl quaternary ammonium salt phase transfer catalyst, base reagent, solvent, water composition system in contract
Close reaction, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate;
(2) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared: by [4-(tertbutyloxycarbonyl) (isopropyl) amino fourth oxygen
Base] tert-butyl acetate puts in the system being made up of base reagent, solvent and water, and be hydrolyzed reaction, obtains [4-(tertiary butyloxycarbonyl
Base) (isopropyl) Aminobutoxy] acetic acid;
(3) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared: by [4-(tertiary butyloxycarbonyl
Base) (isopropyl) Aminobutoxy] acetic acid and methylsulfonamides condensing agent, solvent composition system in carry out condensation reaction, obtain
2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide;
(4) prepare Sai Lexipa: by 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, throw
Enter in the system being made up of the solvent of trifluoroacetic acid and deprotection reaction, carry out deprotection reaction, obtain 2-[4-(isopropyl)
Aminobutoxy]-N-(mesyl) acetamide;Again by 2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide and 5-
Chloro-2,3-diphenyl pyrazine carries out substitution reaction in the system of the solvent composition of acid binding agent alkali and substitution reaction, obtains Sai Lexi
Handkerchief.
Preferably, the quaternary ammonium salt phase transfer catalyst described in step (1) is tetrabutylammonium chloride, tetrabutyl ammonium bromide, the tetrabutyl
Ammonium iodide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, methyl tricapryl ammonium chloride, ten
Dialkyl group trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride;Described base reagent is potassium hydroxide, sodium hydroxide, hydrogen-oxygen
Change lithium, potassium carbonate, sodium carbonate, cesium carbonate or lithium carbonate;Described solvent is dichloromethane, 1,2-dichloroethanes, chloroform, first
Benzene, methyl tertiary butyl ether(MTBE) or acetonitrile;Wherein, 4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol, bromo-acetic acid tert-butyl, season
Mol ratio between ammonium salt phase transfer catalyst, base reagent, solvent, water is 1.0: (1.1~1.5): (0.02~0.05): (1.4~1.8):
(10.0~25.0): (5.0~10.0).
Preferably, the base reagent described in step (2) is sodium hydroxide, potassium hydroxide, Lithium hydrate or Cesium hydrate.;Described
Solvent is methanol, ethanol, isopropanol, normal propyl alcohol, the tert-butyl alcohol or n-butyl alcohol;Wherein, [4-(tertbutyloxycarbonyl) (isopropyl) amino
Butoxy] tert-butyl acetate, base reagent, solvent, mol ratio between water be 1.0: (1.1~1.4): (10.0~25.0): (5.0~10.0).
Preferably, the condensing agent described in step (3) is N, N '-carbonyl dimidazoles, N, N '-dicyclohexylcarbodiimide, N, N '-
DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-hydroxy benzo triazole, 1,8-diaza are double
Ring [5.4.0]-ten one-7-alkene, BTA-N, N, N ', N '-tetramethylurea hexafluorophosphate, O-BTA-N, N, N ', N '-
Tetramethylurea Tetrafluoroboric acid ester, 2-(7-azo BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, hexafluorophosphoric acid benzo
Triazol-1-yl-epoxide tripyrrole alkyl phosphorus or BTA-1-base epoxide three (dimethylamino) phosphorus hexafluorophosphate;Described
Solvent be oxolane, dichloromethane, 1,2-dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide,
Methyl tertiary butyl ether(MTBE) or 1,4-dioxane;Wherein, [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, sulfonyloxy methyl
Mol ratio between amine, condensing agent, solvent is 1.0: (1.1~1.4): (1.1~1.6): (10.0~25.0).
Preferably, the solvent of the deprotection reaction described in step (4) is methanol, ethanol, dichloromethane, ethyl acetate, tetrahydrochysene
Furan, isopropanol or dioxane;Described acid binding agent alkali be N, N-diisopropylethylamine, triethylamine, diethylamine, trimethylamine,
Pyridine, piperidines, DMAP, 2,6-lutidines, aniline, N, N-dimethylaniline, N, N-diethylaniline, three
2-aminopropane., tri-n-butylamine, tetramethyl guanidine, N-methylmorpholine or N-ethylmorpholine;The solvent of described substitution reaction be methanol,
Ethanol, the tert-butyl alcohol, isopropanol or oxolane;Wherein, 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(methylsulfonyl
Base) acetamide, trifluoroacetic acid, the solvent of deprotection reaction, 5-chloro-2,3-diphenyl pyrazine, acid binding agent alkali, substitution reaction molten
Mol ratio between agent is 1.0: (1.1~1.4): (25.0~75.0): (1.1~1.3): (2.0~2.5): (10.0~25.0).
Preferably, the temperature of the condensation reaction described in step (1) is 20~40 DEG C, and the response time is 1~5 hour;Step (2)
The temperature of described hydrolysis is 20~80 DEG C, and the response time is 1~8 hour;The temperature of the condensation reaction described in step (3)
Being 70~110 DEG C, the response time is 16~36 hours;The temperature of the deprotection reaction described in step (4) is 50~80 DEG C, remove-insurance
Protecting the response time is 4~10 hours, and the temperature of described substitution reaction is 80~120 DEG C, and the substitution reaction time is 6~24 hours.
The synthetic method of a kind of Sai Lexipa of the present invention, first with 4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol and
Bromo-acetic acid tert-butyl is raw material, by condensation, hydrolysis, again condensation reaction, prepares N-(mesyl) acetamide side chain
Compound, then deprotection chloro-with 5-2,3-diphenyl pyrazine carries out substitution reaction, prepares Sai Lexipa, this route methods
I.e. starting to avoid the purification introducing pyrazine mother nucleus structure, beneficially intermediate too early and avoiding by-product to produce.
The technical scheme that the present invention provides has following technical effect that one, only makees routinely after having reacted due to each step
Post processing and purification are without column chromatography, and impurity is less, controlled, can directly carry out next step reaction, therefore simplify
Operation, the most each step can obtain higher yield;Its two, process route initiation material and the reagent used of the present invention are easy
, the technical scheme of synthetic reaction is reasonable, can produce the use demand meeting crude drug in a large number, it is adaptable to industrialized production;
Its three, owing to pollutant will not be produced in preparation process, thus environmental protection effect can be embodied.
In a word, the method process route is reasonable, operation is succinct, reagent is easy to get and total recovery is high and is satisfied industrialization and amplifies life
Produce the environmental protection effect requiring and embodying excellence.
Detailed description of the invention
Embodiment 1
A) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared:
4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol (20.0g, 0.09mol) and bromo-acetic acid tert-butyl (21.1g, 0.11mol)
Be dissolved in dichloromethane (90mL), add tetrabutylammonium chloride (0.72g, 2.6mmol), potassium hydroxide (7.3g, 0.13mol) and
Water (12.0g), reactant mixture 25 DEG C stirring reaction 2 hours, reactant liquor vacuum rotary steam is concentrated to dryness, and adds ethyl acetate extraction
Taking, magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, ethanol and isopropyl alcohol mixed solvent recrystallization, obtains [4-(tertbutyloxycarbonyl) (isopropyl)
Aminobutoxy] tert-butyl acetate, light yellow oil (26.6g), yield 89.0%, the reaction equation of this step is as follows:
B) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate (26.0g, 0.075mol) is dissolved in methanol (50mL),
Add sodium hydroxide solution (NaOH=3.3g, 0.08mol;Water 9.0g), it is heated to 80 DEG C and reacts 6 hours, be down to room temperature, warp
Later process and purification, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (20.7g), yield 95.0%, this step
Rapid reaction equation is as follows:
C) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (20.0g, 0.07mol) and N, N '-carbonyl dimidazoles (14.0g,
0.09mol) it is dissolved in oxolane (70mL), stirring, add methylsulfonamides (7.9g, 0.08mol), reactant mixture 90 DEG C
Stirring is reacted 18 hours, and reactant liquor concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry,
Recrystallizing methanol, obtains 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, off-white color solid
(21.2g), yield 83.7%, the reaction equation of this step is as follows:
D) prepare Sai Lexipa: 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide (20.0g,
0.055mol) and be dissolved in methanol (110mL), adding trifluoroacetic acid (6.8g, 0.06mol), 65 DEG C of stirring reactions 6 hours are to instead
Should be complete, reactant liquor is added drop-wise to the water (200mL) of stirring, is cooled to 0 DEG C of crystallize 3 hours, filters, obtains midbody compound
(2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide), is then dissolved in methanol (40mL), adds 5-chloro-2,3-
Diphenyl pyrazine (16.0g, 0.06mol), DIPEA (15.5g, 0.12mol), reactant mixture 100 DEG C stirring
Reacting 8 hours, reactant liquor is down to room temperature, adds water (40mL), is cooled to-10 DEG C of crystallizes 3 hours, filters, get Sai Lexi
Handkerchief, white solid (25.0g), yield 92.3%, the reaction equation of this step is as follows:
Embodiment 2
A) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared:
4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol (23.0g, 0.10mol) and bromo-acetic acid tert-butyl (25.2g, 0.13mol)
It is dissolved in 1,2-dichloroethanes (110mL), add tetrabutyl ammonium bromide (1.1g, 3.5mmol), sodium hydroxide (6.4g, 0.16mol)
With water (14.0g), reactant mixture 30 DEG C stirring reaction 3 hours, reactant liquor vacuum rotary steam is concentrated to dryness, and adds ethyl acetate
Extraction, magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, ethanol and isopropyl alcohol mixed solvent recrystallization, obtains [4-(tertbutyloxycarbonyl) (isopropyl
Base) Aminobutoxy] tert-butyl acetate, light yellow oil (30.3g), yield 88.2%, the same embodiment of reaction equation of this step
1;
B) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate (30.0g, 0.09mol) is dissolved in ethanol (85mL), adds
Enter potassium hydroxide solution (KOH=5.7g, 0.10mol;Water 12g), it is heated to 75 DEG C and reacts 7 hours, be down to room temperature, pass through
Post processing and purification, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, off-white color solid (23.5g), yield
93.7%, the reaction equation of this step is with embodiment 1;
C) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (23.0g, 0.08mol) and N, N '-dicyclohexylcarbodiimide
(22.1g, 0.11mol) is dissolved in chloroform (120mL), stirring, adds methylsulfonamides (9.8g, 0.10mol), reactant mixture
80 DEG C of stirrings are reacted 19 hours, and reactant liquor concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is extremely
Dry, recrystallizing methanol, obtain 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, off-white color is solid
Body (24.8g), yield 85.0%, the reaction equation of this step is with embodiment 1;
D) prepare Sai Lexipa: 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide (24.0g,
0.065mol) and be dissolved in ethanol (160mL), adding trifluoroacetic acid (9.0g, 0.08mol), 70 DEG C of stirring reactions 7 hours are to instead
Should be complete, reactant liquor is added drop-wise to the water (260mL) of stirring, is cooled to 0 DEG C of crystallize 3 hours, filters, obtains midbody compound
(2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide), is then dissolved in ethanol (90mL), adds 5-chloro-2,3-
Diphenyl pyrazine (21.8g, 0.08mol), triethylamine (14.9g, 0.15mol), reactant mixture 100 DEG C stirring reaction 18 hours,
Reactant liquor is down to room temperature, adds water (40mL), is cooled to-10 DEG C of crystallizes 3 hours, filters, get Sai Lexipa, white solid
(29.6g), yield 91.0%, the reaction equation of this step is with embodiment 1.
Embodiment 3
A) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared:
4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol (12g, 0.05mol) and bromo-acetic acid tert-butyl (12.1g, 0.06mol)
It is dissolved in chloroform (70mL), adds tetrabutylammonium iodide (0.5g, 1.3mmol), Lithium hydrate (1.7g, 0.07mol) and water (6.5g),
Reactant mixture 20 DEG C stirring reaction 4 hours, reactant liquor vacuum rotary steam is concentrated to dryness, and adds ethyl acetate extraction, and magnesium sulfate is done
Dry, concentrated by rotary evaporation is the most dry, ethanol and isopropyl alcohol mixed solvent recrystallization, obtains [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]
Tert-butyl acetate, light yellow oil (15.6g), yield 86.8%, the reaction equation of this step is with embodiment 1;
B) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate (15.0g, 0.04mol) is dissolved in isopropanol (40mL),
Add lithium hydroxide solution (LiOH=1.3g, 0.05mol;Water 6.0g), it is heated to 70 DEG C and reacts 8 hours, be down to room temperature, warp
Later process and purification, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, off-white color solid (11.7g), yield
93.0%, the reaction equation of this step is with embodiment 1;
C) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (11.0g, 0.04mol) and 1-(3-dimethylamino-propyl)-3-ethyl
Carbodiimide (8.3g, 0.05mol) is dissolved in acetonitrile (40mL), stirring, adds methylsulfonamides (5.1g, 0.05mol), reaction
95 DEG C of mixture stirring reaction 22 hours, reactant liquor concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, rotation
Steaming is concentrated to dryness, recrystallizing methanol, obtains 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide,
Off-white color solid (11.7g), yield 84.2%, the reaction equation of this step is with embodiment 1;
D) prepare Sai Lexipa: 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide (11.0g,
0.03mol) and be dissolved in dichloromethane (60mL), add trifluoroacetic acid (4.4g, 0.04mol), 50 DEG C of stirring reactions 10 hours
To reaction completely, reactant liquor is added drop-wise to the water (120mL) of stirring, is cooled to 0 DEG C of crystallize 3 hours, filters, obtains intermediate
Compound (2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide), is then dissolved in the tert-butyl alcohol (40mL), adds 5-
Chloro-2,3-diphenyl pyrazine (9.6g, 0.036mol), DMAP (8.1g, 0.07mol), reactant mixture 110 DEG C stirs
Mixing reaction 14 hours, reactant liquor is down to room temperature, adds water (15mL), is cooled to-10 DEG C of crystallizes 3 hours, filters, obtains match
Le Xipa, white solid (13.5g), yield 90.5%, the reaction equation of this step is with embodiment 1.
Embodiment 4
A) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared:
4-[(tertbutyloxycarbonyl) (isopropyl) amino]-n-butyl alcohol (15.0g, 0.065mol) and bromo-acetic acid tert-butyl (17.7g, 0.09mol)
It is dissolved in toluene (70mL), adds 4-butyl ammonium hydrogen sulfate (0.88g, 2.6mmol), potassium carbonate (15.2g, 0.11mol) and water
(9.5g), reactant mixture 40 DEG C stirring reaction 1.5 hours, reactant liquor vacuum rotary steam is concentrated to dryness, and adds ethyl acetate extraction,
Magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, ethanol and isopropyl alcohol mixed solvent recrystallization, obtains [4-(tertbutyloxycarbonyl) (isopropyl) amino
Butoxy] tert-butyl acetate, light yellow oil (19.6g), yield 87.5%, the reaction equation of this step is with embodiment 1;
B) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate (19.0g, 0.055mol) is dissolved in the tert-butyl alcohol (60mL),
Add cesium hydroxide solution (CsOH=11.1g, 0.07mol;Water 8.0g), it is heated to 75 DEG C and reacts 6.5 hours, be down to room temperature,
Through post processing and purification, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, off-white color solid (15.0g), receive
Rate 94.2%, the reaction equation of this step is with embodiment 1;
C) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared:
[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid (15.0g, 0.05mol) and 1,8-diazabicyclo [5.4.0]-ten one
-7-alkene (9.5g, 0.06mol) is dissolved in toluene (80mL), stirring, adds methylsulfonamides (5.7g, 0.06mol), and reaction is mixed
Compound 105 DEG C stirring reaction 16 hours, reactant liquor concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and rotation is steamed
It is concentrated to dryness, recrystallizing methanol, obtains 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, class
White solid (16.6g), yield 87.3%, the reaction equation of this step is with embodiment 1;
D) prepare Sai Lexipa: 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide (16.0g,
0.04mol) and be dissolved in ethyl acetate (130mL), add trifluoroacetic acid (5.7g, 0.05mol), 80 DEG C of stirring reactions 5 hours
To reaction completely, reactant liquor is added drop-wise to the water (150mL) of stirring, is cooled to 0 DEG C of crystallize 3 hours, filters, obtains intermediate
Compound (2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide), is then dissolved in isopropanol (50mL), adds 5-
Chloro-2,3-diphenyl pyrazine (13.5g, 0.05mol), N, N-dimethylaniline (12.2g, 0.10mol), reactant mixture 95 DEG C stirring
Reacting 12 hours, reactant liquor is down to room temperature, adds water (40mL), is cooled to-10 DEG C of crystallizes 3 hours, filters, get Sai Le
Western handkerchief, white solid (19.7g), yield 91.0%, the reaction equation of this step is with embodiment 1.
Claims (9)
1. the synthetic method of Yi Zhong Sai Lexipa, it is characterised in that described method comprises the steps:
(1) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate is prepared: by 4-[(tertbutyloxycarbonyl) (isopropyl)
Amino]-n-butyl alcohol and bromo-acetic acid tert-butyl quaternary ammonium salt phase transfer catalyst, base reagent, solvent, water composition system in contract
Close reaction, obtain [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate;
(2) [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid is prepared: by [4-(tertbutyloxycarbonyl) (isopropyl) amino fourth oxygen
Base] tert-butyl acetate puts in the system being made up of base reagent, solvent and water, and be hydrolyzed reaction, obtains [4-(tertiary butyloxycarbonyl
Base) (isopropyl) Aminobutoxy] acetic acid;
(3) 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide is prepared: by [4-(tertiary butyloxycarbonyl
Base) (isopropyl) Aminobutoxy] acetic acid and methylsulfonamides condensing agent, solvent composition system in carry out condensation reaction, obtain
2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide;
(4) prepare Sai Lexipa: by 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, throw
Enter in the system being made up of the solvent of trifluoroacetic acid and deprotection reaction, carry out deprotection reaction, obtain 2-[4-(isopropyl)
Aminobutoxy]-N-(mesyl) acetamide;Again by 2-[4-(isopropyl) Aminobutoxy]-N-(mesyl) acetamide and 5-
Chloro-2,3-diphenyl pyrazine carries out substitution reaction in the system of the solvent composition of acid binding agent alkali and substitution reaction, obtains Sai Lexi
Handkerchief.
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the quaternary ammonium salt described in step (1)
Phase transfer catalyst is tetrabutylammonium chloride, tetrabutyl ammonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, benzyl three second
Ammonium chloride, benzyl triethyl ammonium bromide, methyl tricapryl ammonium chloride, Dodecyl trimethyl ammonium chloride or CPC
Ammonium chloride;Described base reagent is potassium hydroxide, sodium hydroxide, Lithium hydrate, potassium carbonate, sodium carbonate, cesium carbonate or carbon
Acid lithium;Described solvent is dichloromethane, 1,2-dichloroethanes, chloroform, toluene, methyl tertiary butyl ether(MTBE) or acetonitrile;Wherein, 4-[(uncle
Butoxy carbonyl) (isopropyl) amino]-n-butyl alcohol, bromo-acetic acid tert-butyl, quaternary ammonium salt phase transfer catalyst, base reagent, solvent, water it
Between mol ratio be 1.0: (1.1~1.5): (0.02~0.05): (1.4~1.8): (10.0~25.0): (5.0~10.0).
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the base reagent described in step (2)
For sodium hydroxide, potassium hydroxide, Lithium hydrate or Cesium hydrate.;Described solvent be methanol, ethanol, isopropanol, normal propyl alcohol,
The tert-butyl alcohol or n-butyl alcohol;Wherein, [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] tert-butyl acetate, base reagent, solvent,
Mol ratio between water is 1.0: (1.1~1.4): (10.0~25.0): (5.0~10.0).
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the condensing agent described in step (3)
For N, N '-carbonyl dimidazoles, N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1-(3-dimethylamino third
Base)-3-ethyl carbodiimide, 1-hydroxy benzo triazole, 1,8-diazabicyclo [5.4.0]-ten one-7-alkene, BTA
-N, N, N ', N '-tetramethylurea hexafluorophosphate, O-BTA-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester, 2-(7-azo
BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl phosphorus or
BTA-1-base epoxide three (dimethylamino) phosphorus hexafluorophosphate;Described solvent be oxolane, dichloromethane,
1,2-dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, methyl tertiary butyl ether(MTBE) or 1,4-dioxane;
Wherein, the mol ratio between [4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy] acetic acid, methylsulfonamides, condensing agent, solvent
It is 1.0: (1.1~1.4): (1.1~1.6): (10.0~25.0).
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the deprotection described in step (4)
The solvent of reaction is methanol, ethanol, dichloromethane, ethyl acetate, oxolane, isopropanol or dioxane;Described ties up
Acid agent alkali is N, N-diisopropylethylamine, triethylamine, diethylamine, trimethylamine, pyridine, piperidines, DMAP, 2,6-
Lutidines, aniline, N, N-dimethylaniline, N, N-diethylaniline, Tris(isopropylamine)., tri-n-butylamine, tetramethyl guanidine, N-
Methyl morpholine or N-ethylmorpholine;The solvent of described substitution reaction is methanol, ethanol, the tert-butyl alcohol, isopropanol or oxolane;
Wherein, 2-[4-(tertbutyloxycarbonyl) (isopropyl) Aminobutoxy]-N-(mesyl) acetamide, trifluoroacetic acid, deprotection reaction
Solvent, 5-chloro-2,3-diphenyl pyrazine, acid binding agent alkali, substitution reaction solvent between mol ratio be 1.0: (1.1~1.4):
(25.0~75.0): (1.1~1.3): (2.0~2.5): (10.0~25.0).
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the condensation described in step (1) is anti-
The temperature answered is 20~40 DEG C, and the response time is 1~5 hour.
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the hydrolysis described in step (2) is anti-
The temperature answered is 20~80 DEG C, and the response time is 1~8 hour.
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the condensation described in step (3) is anti-
The temperature answered is 70~110 DEG C, and the response time is 16~36 hours.
The synthetic method of a kind of Sai Lexipa the most according to claim 1, it is characterised in that the deprotection described in step (4)
The temperature of reaction is 50~80 DEG C, and the deprotection reaction time is 4~10 hours, and the temperature of described substitution reaction is 80~120 DEG C,
The substitution reaction time is 6~24 hours.
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CN108069914A (en) * | 2016-11-17 | 2018-05-25 | 江苏艾立康药业股份有限公司 | A kind of preparation method of West pa lattice crystal form |
CN108440421A (en) * | 2018-05-14 | 2018-08-24 | 湖南华腾制药有限公司 | A kind of deuterated Sai Lexipa and preparation method thereof |
CN108558653A (en) * | 2018-05-14 | 2018-09-21 | 湖南华腾制药有限公司 | The preparation method of Sai Lexipa intermediates and Sai Lexipa |
CN108774182A (en) * | 2018-07-11 | 2018-11-09 | 湖南华腾制药有限公司 | A kind of process for purification of Sai Lexipa |
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CN112939877A (en) * | 2019-12-11 | 2021-06-11 | 南京理工大学 | Synthesis method of diphenylpyrazine derivative |
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CN109384734A (en) * | 2017-08-14 | 2019-02-26 | 上海科胜药物研发有限公司 | A kind of preparation method of Sai Erxipa intermediate |
CN109384734B (en) * | 2017-08-14 | 2023-04-11 | 上海科胜药物研发有限公司 | Preparation method of Selsemipa intermediate |
CN108440421A (en) * | 2018-05-14 | 2018-08-24 | 湖南华腾制药有限公司 | A kind of deuterated Sai Lexipa and preparation method thereof |
CN108558653A (en) * | 2018-05-14 | 2018-09-21 | 湖南华腾制药有限公司 | The preparation method of Sai Lexipa intermediates and Sai Lexipa |
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