CN107652243A - A kind of preparation method of West pa lattice intermediate - Google Patents
A kind of preparation method of West pa lattice intermediate Download PDFInfo
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- CN107652243A CN107652243A CN201710824916.2A CN201710824916A CN107652243A CN 107652243 A CN107652243 A CN 107652243A CN 201710824916 A CN201710824916 A CN 201710824916A CN 107652243 A CN107652243 A CN 107652243A
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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
Abstract
The present invention relates to a kind of preparation method of West pa lattice intermediate, belong to chemical preparation field.The West pa lattice intermediate of the present invention is 4 [N (base of 5,6 diphenyl piperazine 2) N isopropylaminos] 1 butanol, and its preparation method comprises the following steps：The diphenyl pyrazine of 5 chlorine 2,3 and 4 (isopropylamino) 1 butanol are dissolved in organic solvent, reacted in the presence of palladium catalyst, complex catalyst and alkali, obtains the West pa lattice intermediate.The preparation method of pa lattice intermediate in West of the present invention prepares simplicity, and reaction condition is gentle, environment-friendly, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of West pa lattice intermediate, belong to chemical preparation field.
Background technology
Selexipag (West pa lattice), chemical name is：2- { 4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropyls
Amino] butoxy }-N- (mesyl) acetamide, its No. CAS is：475086-01-2, structural formula are as follows：
Yuan Yan producers Actelion Ltd, on December 21st, 2015, U.S.'s food and Drug Administration office (FDA) have approved orphan
Youngster's medicine Selexipag (Uptravi) is used for the treatment of adult pulmonary's high pressure.Pulmonary hypertension is a kind of chronic progressive lung
Disease, prognosis is bad, and patient premature death or may need lung transplantation.Selexipag is a kind of oral Ip prostacyclins
Receptor stimulating agent, can relax vascular smooth muscle, expand blood vessel, reduce pulmonary artery pressure.
4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropylaminos]-n-butyl alcohol is the important of Selexipag synthesis
Intermediate, structure such as formula A：
At present, the preparation method of the compound has two kinds, as follows：
Method one：According to Bioorg.Med.Chem.2007,15,6692.＆J.Am.Soc.Chem.1952,74,1580
A kind of synthesis technique is provided with patent WO02088084A1, it is as follows：
Method one is with compound (4- (isopropyls shown in compound shown in formula I (the chloro- 2,3- diphenyl pyrazines of 5-) and formula II
Amino)-n-butyl alcohol) it is raw material, react 10 hours, cool under 190 DEG C of high temperature, add water, ether extraction, dry concentration, then use
Silica gel column chromatography refines, and obtains product, yield 57%.The shortcomings that this method is：With compound 4- (isopropylamino) -1- fourths
Alcohol is nearly 9 times of chloro- 2, the 3- diphenyl pyrazines moles of 5- as raw material and solvent, usage amount, causes raw material largely to waste, and is closed
It is too high into cost, and yield is low, only 57%；Reaction temperature is 190 DEG C, oil bath need to be used, to consersion unit and environmental requirement
It is higher, and energy consumption is too high；Product is refined using silica gel chromatography, is unfavorable for industrializing.
Method two：A kind of synthesis technique is provided according to patent WO2011024874A1, it is as follows：
Method two with compound shown in formula I (chloro- 2, the 3- diphenyl pyrazines of 5-) for raw material, Mr. in the presence of sodium iodide
React, made of 1-METHYLPYRROLIDONE (NMP) molten into iodo- 2, the 3- diphenyl pyrazines of 5-, then with 4- (isopropylamino)-n-butyl alcohol
Agent, in the presence of potassium carbonate 170 DEG C of synthesis obtain product.The shortcomings that technique is：The iodo- 2,3- diphenyl pyrroles of 5- need to first be prepared
Piperazine, increased processing step, make its preparation technology more cumbersome；Second step is high using boiling point, the big 1-METHYLPYRROLIDONE of toxicity
(NMP) solvent is made, pollutes environment；Second step reaction temperature is 170 DEG C, need to use oil bath, to consersion unit and environmental requirement compared with
Height, and energy consumption is too high, is not suitable for industrialized production.
As can be seen here, in the preparation technology of 4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropylaminos]-n-butyl alcohol
Have the following disadvantages：The cost of material of method one is high, and yield is low, and reaction temperature is high, and equipment requirement is high, high energy consumption, is unfavorable for industry
Change；The preparation technology of method two is cumbersome, and reaction temperature is high, and equipment requirement is high, high energy consumption, and solvent N-methyl pyrilidone (NMP)
Boiling point is high, and toxicity is big, is not suitable for industrialized production.
The content of the invention
There is provided that a kind of reaction condition is gentle, product it is an object of the invention to overcome in place of above-mentioned the deficiencies in the prior art
The preparation side of 4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropylaminos]-n-butyl alcohol with high-purity and in high yield
Method.
To achieve the above object, the technical scheme taken of the present invention is：A kind of preparation method of West pa lattice intermediate, institute
West pa lattice intermediate is stated as 4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropylaminos]-n-butyl alcohol (structure such as formula A institutes
Show), its preparation method comprises the following steps：By the chloro- 2,3- diphenyl pyrazines of 5- (structure is as shown in formula I) and 4- (isopropyl ammonia
Base) it is dissolved in organic solvent in-n-butyl alcohol (structure is as shown in formula ∏), in the effect of palladium catalyst, complex catalyst and alkali
Lower reaction, obtain the West pa lattice intermediate.Reaction equation is as follows：
When the present invention prepares West pa lattice intermediate, in the presence of palladium catalyst, organophosphor ligand and alkali, 5- chloro- 2,
When 3- diphenyl pyrazines and 4- (isopropylamino)-n-butyl alcohol generation coupling reaction prepare the intermediate, rapid reaction, reaction
Mild condition, for example, reaction temperature can be reduced to 60-120 DEG C from 170 DEG C, chloro- 2, the 3- diphenyl pyrazines of 5- and 4- (isopropyls
Base amino)-n-butyl alcohol carries out the reaction that feeds intake with certain equivalents.Also, research shows, in this approach the receipts of obtained product
Rate is more than 90%, and the purity of product is higher.
In above-mentioned preparation method, with detection reaction entirely as terminal, stop reaction.For example, reacted using TLC detections
Entirely, reaction is stopped.Generally, the reaction time is 2~6 hours.
As the preferred embodiment of the preparation method of pa lattice intermediate in West of the present invention, the temperature of the reaction is
60-120℃。
As the more preferably embodiment of the preparation method of pa lattice intermediate in West of the present invention, the temperature of the reaction
For 70-90 DEG C.
As the preferred embodiment of the preparation method of pa lattice intermediate in West of the present invention, in following (a)~(d)
At least one of：
(a) palladium catalyst is Pd (dba)2, Pd2(dba)3Or Pd (OAc)2；
(b) organophosphor ligand is 1,1'- dinaphthalenes -2,2'- double diphenyl phosphine (BINAP), tri-butyl phosphine (P (t-Bu
)3), three (o-methyl-phenyl) phosphorus (P (o-tolyl)3) or double (the diphenylphosphine) -9,9- dimethyl xanthenes (Xantphos) of 4,5-
Deng；
(c) alkali is cesium carbonate, potassium carbonate, potassium tert-butoxide or sodium tert-butoxide；
(d) organic solvent is toluene or 1,4- dioxane.
As the preferred embodiment of the preparation method of pa lattice intermediate in West of the present invention, chloro- 2, the 3- bis- of 5-
The mol ratio of phenyl pyrazines and 4- (isopropylamino)-n-butyl alcohol is 1：1~1：3；The chloro- 2,3- diphenyl pyrazines of the 5- and palladium
The mass ratio of catalyst is 1：0.01~1：0.1；The mol ratio of Pd and organophosphor ligand is 1 in the palladium catalyst：1~1：3；
The mol ratio of the chloro- 2,3- diphenyl pyrazines of the 5- and alkali is 1：1~1：3.As pa lattice intermediate in West of the present invention
The mass ratio of the more preferably embodiment of preparation method, chloro- 2, the 3- diphenyl pyrazines of the 5- and palladium catalyst is 1：0.01~
1：0.05；The mol ratio of Pd and organophosphor ligand is 1 in the palladium catalyst：1~1：2.
Chloro- 2, the 3- diphenyl pyrazines of 5- and 4- (isopropylamino)-n-butyl alcohol can occur under the conditions of certain fierceness
Substitution reaction generates target product 4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropylaminos]-n-butyl alcohol, under high temperature
React (170 DEG C of reaction temperature), with large excess of 4- (isopropylamino)-n-butyl alcohol.Methods described herein is effectively kept away
These shortcomings are exempted from, using transition metal palladium and organic ligand, in the presence of catalytic amount, have made chloro- 2, the 3- diphenyl pyrazines of 5-
Can be under conditions of 4- (isopropylamino)-n-butyl alcohol of relatively low temperature and equivalent proportion with 4- (isopropylamino)-n-butyl alcohol
Carry out that coupling reaction generation target product 4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropylaminos]-n-butyl alcohol occurs.
Because the transition metal palladium and organic ligand that use are catalytic amount, it is the 1%~5% of starting material, post-reaction treatment can be made
Purifying greatly simplifies.
As the preferred embodiment of the preparation method of pa lattice intermediate in West of the present invention, the preparation method is also wrapped
Include following steps：After reaction terminates, filtering, and acid solution is added to adjust the pH value of filtrate to 6.5~7.5 into filtrate, then
Add extractant to be extracted, washing extraction products therefrom, and be dried, concentrate and recrystallize, obtain in the pa lattice of West
Mesosome.By extracting and product is further purified in recrystallization, the purity of gained West pa lattice intermediate is drastically increased, its is pure
Degree up to more than 99%.
As the preferred embodiment of the preparation method of pa lattice intermediate in West of the present invention, the extractant is second
Acetoacetic ester or dichloromethane.
As the preferred embodiment of the preparation method of pa lattice intermediate in West of the present invention, the solvent of the recrystallization
The mixed solvent being made up of alcohols solvent and alkane solvents.
As the more preferably embodiment of the preparation method of pa lattice intermediate in West of the present invention, the alcohols solvent is
Methanol, ethanol or isopropanol；The alkane solvents are pentane, hexane or heptane.
As the more preferably embodiment of the preparation method of pa lattice intermediate in West of the present invention, the alcohols solvent with
The volume ratio of alkane solvents is 1：3~1：20；Preferably, the volume ratio of the alcohols solvent and alkane solvents is 1：5~
1：10.
In purifying products scheme of the present invention, alcohols solvent is good solvent, and the increase of ratio is advantageous to going for impurity
Remove, alkane solvents are poor solvent, and the increase of ratio is advantageous to improve yield, controls in suitable volume ratio, be advantageous to
To in high yield, the product of high-purity.
Compared with prior art, beneficial effects of the present invention are：The chloro- 2,3- diphenyl pyrazines of 5- and 4- (isopropyl ammonia
Base) mol ratio of-n-butyl alcohol can be fed intake by stoichiometric ratio, avoid using large excess of 4- (isopropylamino)-
N-butyl alcohol, cost is saved, makes post-processing approach more easy, be adapted to technique amplification and industrialization production.Especially, palladium is employed
Catalyst, organophosphor ligand feed intake for catalytic amount, and reaction temperature can be reduced to 60-120 DEG C from 170 DEG C, and improve reaction
Speed, substantially increase technique can amplification.The preparation method of the present invention is reasonable in design, and easy to operate, cost of material is low, nothing
Special installation is needed, and energy consumption is low, post processing is easy, is adapted to industrialized production.
Embodiment
For the object, technical solutions and advantages of the present invention are better described, below in conjunction with specific embodiment to the present invention
It is described further.
Embodiment 1
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (22.0g, 0.17mol, 1.5eq.), Isosorbide-5-Nitrae-dioxy
Six ring 150mL, stirring and dissolving, sequentially add Pd (dba)2(0.65g, 1.13mmol), BINAP (1.05g, 1.69mmol),
Sodium tert-butoxide (13.0g, 0.135mol), 90 DEG C are heated to, insulation reaction 2 hours, TLC detection reactions are complete, stop anti-
Should.Room temperature is cooled to, is filtered, filtrate adjusts pH value to 6.5-7.5 with 1N hydrochloric acid, is extracted with ethyl acetate (150mL × 2),
150mL salt water washings, anhydrous sodium sulfate drying, decompression boil off solvent, residue ethanol：N-hexane=1:5 mixed solvents
300mL recrystallize, oven drying, obtain target compound 4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropylaminos] -
N-butyl alcohol, 38.30g off-white powders, yield 94%, liquid phase purity 99.3%.
The product obtained by the present embodiment is characterized using HNMR, is as a result (nuclear magnetic data)：1H-NMR(400MHz,
CDCl3),δppm：8.03 (s, 1H), 7.47 (d, J=7.6Hz, 2H), 7.35 (d, J=7.2Hz, 2H), 7.29-7.21 (m,
6H), 4.81-4.78 (m, 1H), 3.71 (t, J=6.4Hz, 2H), 3.45 (t, J=7.6Hz, 2H), 1.76-1.72 (m, 2H),
1.66-1.63 (m, 2H), 1.29 (d, J=6.8Hz, 6H).As can be seen here, the product of gained be target compound 4- [N- (5,
6- diphenyl piperazine -2- bases)-N- isopropylaminos]-n-butyl alcohol.
Embodiment 2
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (22.0g, 0.17mol, 1.5eq.), toluene
150mL, stirring and dissolving, sequentially add Pd (dba)2(0.65g, 1.13mmol), BINAP (1.05g, 1.69mmol), tertiary fourth
Sodium alkoxide (13.0g, 0.135mol), 90 DEG C are heated to, insulation reaction 2 hours, TLC detection reactions are complete, stop reaction.Drop
Warm to room temperature, filter, filtrate is extracted, 150mL salt with ethyl acetate (150mL × 2) with 1N salt acid for adjusting pH value to 6.5-7.5
Water washing, anhydrous sodium sulfate drying, decompression boil off solvent, residue ethanol：N-hexane=1:5 mixed solvent 300mL are tied again
Crystalline substance, oven drying, obtain 36.6g off-white powders, yield 90%, liquid phase purity 99.5%.
Embodiment 3
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (22.0g, 0.17mol, 1.5eq.), Isosorbide-5-Nitrae-dioxy
Six ring 150mL, stirring and dissolving, sequentially add Pd (OAc)2(0.74g, 3.3mmol), P (t-Bu)3(1.33g, 6.6mmol),
Sodium tert-butoxide (13.0g, 0.135mol), 90 DEG C are heated to, insulation reaction 5 hours, TLC detection reactions are complete, stop anti-
Should.Room temperature is cooled to, is filtered, filtrate is extracted with ethyl acetate (150mL × 2) with 1N salt acid for adjusting pH value to 6.5-7.5,
150mL salt water washings, anhydrous sodium sulfate drying, decompression boil off solvent, residue ethanol：N-hexane=1:5 mixed solvents
300mL is recrystallized, and oven drying, obtains 37.5g off-white powders, yield 92%, liquid phase purity 99.3%.
Embodiment 4
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (16.2g, 0.12mol, 1.1eq.), toluene
150mL, stirring and dissolving, sequentially add Pd2(dba)3(0.6g, 0.65mmol), P (o-tolyl)3(0.85g, 4.2mmol),
Cesium carbonate (43.0g, 0.13mol), 70 DEG C are heated to, insulation reaction 3 hours, TLC detection reactions are complete, stop reaction.
Room temperature is cooled to, is filtered, filtrate is extracted, 150mL with dichloromethane (150mL × 2) with 1N salt acid for adjusting pH value to 6.5-7.5
Salt water washing, anhydrous sodium sulfate drying, decompression boil off solvent, residue ethanol：N-hexane=1:5 mixed solvent 300mL weights
Crystallization, oven drying, obtains 37.0g off-white powders, yield 91%, liquid phase purity 99.2%.
Embodiment 5
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (29.5g, 0.22mol, 2.0eq.), toluene
150mL, stirring and dissolving, sequentially add Pd (dba)2(0.3g, 0.52mmol), Xantphos (0.6,1.04mmol), tertiary fourth
Potassium alcoholate (14.8g, 0.13mol), 80 DEG C are heated to, insulation reaction 2.5 hours, TLC detection reactions are complete, stop reaction.
Room temperature is cooled to, is filtered, filtrate is extracted, 150mL with dichloromethane (150mL × 2) with 1N salt acid for adjusting pH value to 6.5-7.5
Salt water washing, anhydrous sodium sulfate drying, decompression boil off solvent, residue ethanol：N-hexane=1:5 mixed solvent 300mL weights
Crystallization, oven drying, obtains 37.5g off-white powders, yield 92%, liquid phase purity 99.4%.
Embodiment 6
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (44.0g, 0.34mol, 3.0eq.), Isosorbide-5-Nitrae-dioxy
Six ring 150mL, stirring and dissolving, sequentially add Pd (dba)2(0.9g, 1.66mmol), BINAP (1.55g, 2.49mmol), uncle
Sodium butoxide (13.0g, 0.135mol), 60 DEG C are heated to, insulation reaction 4 hours, TLC detection reactions are complete, stop reaction.
Room temperature is cooled to, is filtered, filtrate is extracted, 150mL with ethyl acetate (150mL × 2) with 1N salt acid for adjusting pH value to 6.5-7.5
Salt water washing, anhydrous sodium sulfate drying, decompression boil off solvent, residue ethanol：N-hexane=1:3 mixed solvent 300mL weights
Crystallization, oven drying, obtains 36.6g off-white powders, yield 90%, liquid phase purity 99.5%.
Embodiment 7
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (18.5g, 0.14mol, 1.25eq.), Isosorbide-5-Nitrae-two
The ring 150mL of oxygen six, stirring and dissolving, sequentially adds Pd (dba)2(2.4g, 4.2mmol), P (o-tolyl)3(1.69g,
8.3mmol), sodium tert-butoxide (13.0g, 0.135mol), 120 DEG C are heated to, insulation reaction 1.8 hours, TLC detections are reacted
Completely, reaction is stopped.Room temperature is cooled to, is filtered, filtrate is with 1N salt acid for adjusting pH value to 6.5-7.5, with ethyl acetate (150mL
× 2) extract, 150mL salt water washings, anhydrous sodium sulfate drying, decompression boils off solvent, residue ethanol：N-hexane=1:15
Mixed solvent 300mL is recrystallized, and oven drying, obtains 39.0g off-white powders, yield 96%, liquid phase purity 97.1%.
Embodiment 8
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (18.5g, 0.14mol, 1.25eq.), Isosorbide-5-Nitrae-two
The ring 150mL of oxygen six, stirring and dissolving, sequentially adds Pd (dba)2(3g, 5.25mmol), P (o-tolyl)3(3.21g,
15.75mmol), sodium tert-butoxide (10.59g, 0.11mol), 90 DEG C are heated to, insulation reaction 2 hours, TLC detections are reacted
Completely, reaction is stopped.Room temperature is cooled to, is filtered, filtrate is with 1N salt acid for adjusting pH value to 6.5-7.5, with ethyl acetate (150mL
× 2) extract, 150mL salt water washings, anhydrous sodium sulfate drying, decompression boils off solvent, residue ethanol：N-hexane=1:20
Mixed solvent 300mL is recrystallized, and oven drying, obtains 38.2g off-white powders, yield 94%, liquid phase purity 95.7%.
Embodiment 9
A kind of embodiment of the preparation method of pa lattice intermediate in West of the present invention, pa lattice intermediate in West described in the present embodiment
Preparation method be：Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrroles of 5- are sequentially added
Piperazine (30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (14.5g, 0.11mol, 1.0eq.), Isosorbide-5-Nitrae-dioxy
Six ring 150mL, stirring and dissolving, sequentially add Pd (dba)2(1.5g, 2.62mmol), P (o-tolyl)3(0.53g,
2.62mmol), sodium tert-butoxide (31.8g, 0.33mol), 90 DEG C are heated to, insulation reaction 2 hours, TLC detections have been reacted
Entirely, reaction is stopped.Be cooled to room temperature, filter, filtrate with 1N salt acid for adjusting pH value to 6.5-7.5, with ethyl acetate (150mL ×
2) extract, 150mL salt water washings, anhydrous sodium sulfate drying, decompression boils off solvent, residue ethanol：N-hexane=1:10 is mixed
Bonding solvent 300mL is recrystallized, and oven drying, obtains 39.0g off-white powders, yield 92%, liquid phase purity 98.5%.
Applicant is also characterized using HNMR to the product of the gained of embodiment 2~9, as a result with the result phase of embodiment 1
Unanimously, it was demonstrated that the product of the gained of embodiment 2~9 is target compound 4- [N- (5,6- diphenyl piperazine -2- bases)-N- isopropyls
Amino]-n-butyl alcohol.Do not repeat experimental data one by one herein.
Embodiment 10
Equipped with return duct, in the reaction bulb of drying tube and thermometer, chloro- 2, the 3- diphenyl pyrazines of 5- are sequentially added
(30.0g, 0.11mol, 1.0eq.), 4- (isopropylamino)-n-butyl alcohol (22.0g, 0.17mol, 1.5eq.), Isosorbide-5-Nitrae-dioxy six
Ring 150mL, stirring and dissolving, sequentially add Pd (dba)2(0.65g, 1.13mmol), BINAP (1.05g, 1.69mmol), uncle
Sodium butoxide (13.0g, 0.135mol), 90 DEG C are heated to, insulation reaction 2 hours, TLC detection reactions are complete, stop reaction.
Room temperature is cooled to, is filtered, filtrate is extracted, 150mL salt solution with ethyl acetate (150mL × 2) with 1N salt acid for adjusting pH value to 7-8
Washing, anhydrous sodium sulfate drying, decompression boil off solvent, obtain 45g residues, and residue is divided into 9 parts, 5 grams every part, with difference
Mixed solvent recrystallized, concrete outcome such as table 1 below.
Table 1
From table 1, the selection of the solvent of recrystallization influences yield and product purity, controls alcohols solvent and alkanes molten
The ratio of agent, be advantageous to obtain in high yield, the product of high-purity.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than the present invention is protected
The limitation of scope is protected, although being explained in detail with reference to preferred embodiment to the present invention, one of ordinary skill in the art should
Understand, technical scheme can be modified or equivalent substitution, without departing from the essence of technical solution of the present invention
And scope.
Claims (10)
- A kind of 1. preparation method of West pa lattice intermediate, it is characterised in that：The West pa lattice intermediate is 4- [N- (5,6- Diphenyl piperazine -2- bases)-N- isopropylaminos]-n-butyl alcohol, its preparation method comprises the following steps：By the chloro- 2,3- hexichol of 5- Base pyrazine and 4- (isopropylamino)-n-butyl alcohol are dissolved in organic solvent, in the effect of palladium catalyst, organophosphor ligand and alkali Lower reaction, obtain the West pa lattice intermediate.
- 2. the preparation method of pa lattice intermediate in West as claimed in claim 1, it is characterised in that：The temperature of the reaction is 60-120℃。
- 3. the preparation method of pa lattice intermediate in West as claimed in claim 2, it is characterised in that：The temperature of the reaction is 70-90℃。
- 4. the preparation method of pa lattice intermediate in West as claimed in claim 1, it is characterised in that：As follows in (a)~(d) extremely One item missing：(a) palladium catalyst is Pd (dba)2, Pd2(dba)3Or Pd (OAc)2；(b) organophosphor ligand be the double diphenyl phosphines of 1,1'- dinaphthalenes -2,2'-, tri-butyl phosphine, three (o-methyl-phenyl) phosphorus or Double (the diphenylphosphine) -9,9- dimethyl xanthenes of 4,5-；(c) alkali is cesium carbonate, potassium carbonate, potassium tert-butoxide or sodium tert-butoxide；(d) organic solvent is toluene or 1,4- dioxane.
- 5. the preparation method of the West pa lattice intermediate as described in claim 1 or 4, it is characterised in that：The chloro- 2,3- bis- of 5- The mol ratio of phenyl pyrazines and 4- (isopropylamino)-n-butyl alcohol is 1：1~1：3；The chloro- 2,3- diphenyl pyrazines of the 5- and palladium The mass ratio of catalyst is 1：0.01~1：0.1；The mol ratio of Pd and organophosphor ligand is 1 in the palladium catalyst：1~1：3； The mol ratio of the chloro- 2,3- diphenyl pyrazines of the 5- and alkali is 1：1~1：3.
- 6. the preparation method of pa lattice intermediate in West as claimed in claim 5, it is characterised in that：The chloro- 2,3- hexichol of 5- The mass ratio of base pyrazine and palladium catalyst is 1：0.01~1：0.05；The mol ratio of Pd and organophosphor ligand in the palladium catalyst For 1：1~1：2.
- 7. the preparation method of the West pa lattice intermediate as described in any one of claim 1~6, it is characterised in that：Also include with Lower step：After reaction terminates, filtering, and acid solution is added to adjust the pH value of filtrate to 6.5~7.5 into filtrate, add Extractant is extracted, washing extraction products therefrom, and is dried, concentrates and is recrystallized, and obtains West pa lattice intermediate.
- 8. the preparation method of pa lattice intermediate in West as claimed in claim 7, it is characterised in that：The solvent of the recrystallization is The mixed solvent being made up of alcohols solvent and alkane solvents.
- 9. the preparation method of pa lattice intermediate in West as claimed in claim 8, it is characterised in that：The alcohols solvent is first Alcohol, ethanol or isopropanol；The alkane solvents are pentane, hexane or heptane.
- 10. the preparation method of pa lattice intermediate in West as claimed in claim 8 or 9, it is characterised in that：The alcohols solvent with The volume ratio of alkane solvents is 1：3~1：20；Preferably, the volume ratio of the alcohols solvent and alkane solvents is 1：5~ 1：10.
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