CN106892905A - A kind of preparation method of Lei Dipawei - Google Patents
A kind of preparation method of Lei Dipawei Download PDFInfo
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract
The invention belongs to pharmaceutical synthesis field, more particularly to a kind of preparation method of Lei Dipawei comprises the following steps：Compound (II) and compound (III) react to obtain compound (IV) under alkali effect；Compound (IV) and compound (V) react to obtain compound (VI) under metallic catalyst effect；Compound (VI) carries out ring-closure reaction and obtains compound (VII) with amine reagent；Compound (VII) obtains compound (VIII) under acid effect；Compound (VIII) obtains the Lei Dipawei of chemical formula (I) with Moc-L- valines under condensing agent effect.Present invention process route step line is short, and easy to operate, reaction yield is high.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, more particularly to a kind of preparation method of Lei Dipawei.
Background technology
Lei Dipawei, English name：Ledipasvir, chemical name：Methyl N- [(2S) -1- [(6S) -6- [5- [9,
9-Difluoro-7-[2-[(1S,2S,4R)-3-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-3-azabicyclo[2
.2.1]heptan-2-yl]-3H-benzimidazol-5-yl]fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]heptan-5-y
L] -3-methyl-1-oxobutan-2-yl] carbamate, chemical structural formula is as follows：
Lei Dipawei is one of composition of compound combination of the anti-hepatitis hit product Harvoni of lucky moral, and NS5A inhibitor suppresses
Agent.Harvoni is the anti-HCV medicament that the lucky moral in the U.S. is developed, and is first and ratifies for the type hepatitis C infections of therapeutic gene 1,
And the complete oral anti-hepatitis scheme of interferon or Ribavirin need not be combined.Harvoni both can single medicine use, it is also possible to and its
Its oral formulations such as ribavirin combination is used.Harvoni obtains FDA " preferential evaluation " qualification, is also the 7th acquisition
The medicine of " breakthrough medicine " qualification.
WO201384702A discloses a kind of preparation technology of Lei Dipawei, as follows：
The process route has that synthesis technique is cumbersome, route is long, the low shortcoming of reaction yield, is not suitable for industrial production on a large scale.
The content of the invention
The purpose of the present invention is：Solve that existing Lei Dipawei synthetic routes are long, the low problem of reaction yield, there is provided one kind synthesis
The preparation method of the Lei Dipawei that route is short, reaction yield is high.
Realizing the technical scheme of the object of the invention is：A kind of preparation method of Lei Dipawei, the Lei Dipawei structures such as chemical formula
(I)
With following steps：
(1) compound of the compound of chemical formula (II) and chemical formula (III) reaction under alkali effect obtains chemical formula (IV)
Compound：
(2) compound of the compound of chemical formula (IV) and chemical formula (V) reaction under metallic catalyst effect obtains chemical formula
(VI) compound：
(3) compound of chemical formula (VI) carries out the compound that ring-closure reaction obtains chemical formula (VII) with amine reagent：
(4) compound of chemical formula (VII) obtains the compound of chemical formula (VIII) under acid effect：
(5) compound of chemical formula (VIII) obtains the compound of chemical formula (I) with Moc-L- valines under condensing agent effect.
Wherein,
A, E, X, Y are defined as follows：
When A is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, E is tertbutyloxycarbonyl, then X is hydrogen, and Y is (S) -2- (first
Epoxide carbonyl amino) -3- methylbutyraldehyd bases, n is 3；Or
When A is tertbutyloxycarbonyl, E is tertbutyloxycarbonyl, then X is hydrogen, and Y is hydrogen, and n is 4；Or
When A is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, E is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases,
Then X is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, and Y is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, n
It is 0.
In the step (1), alkali used is potassium carbonate, and solvent for use is acetonitrile.
In the step (2), metallic catalyst used is tetra-triphenylphosphine palladium, and solvent for use is isopropyl acetate.
In the step (3), amine reagent used is Ammoniom-Acetate, and solvent for use is toluene.
In the step (4), acid used is hydrochloric acid, and solvent for use is ethanol or acetonitrile.
In the step (5), condensing agent HOBt and EDCI used, solvent for use is DMF and N- methyl
Morpholine.
Described A is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, and E is tertbutyloxycarbonyl, and processing step is：
(1) compound of the compound of chemical formula (II) and chemical formula (III) reaction under alkali effect obtains chemical formula (IV)
Compound：
(2) change
The reaction under metallic catalyst effect of the compound of the compound of formula (IV) and chemical formula (V) obtains chemical formula (VI)
Compound：
(3) compound of chemical formula (VI) carries out the compound that ring-closure reaction obtains chemical formula (VII) with amine reagent：
(4) compound of chemical formula (VII) obtains the compound of chemical formula (VIII) under acid effect：
(5) compound of chemical formula (VIII) obtains the chemical combination of chemical formula (I) with Moc-L- valines under condensing agent effect
Thing.
The step (1) is after compound (II), compound (III), acetonitrile stir in there-necked flask, to add carbon
Sour potassium, is heated to 50 DEG C and reacts 4-6 hours, and reaction terminates to add water, is cooled to room temperature mashing, and filtering, washing is dry to change
Compound (IV)；
The step (2) is that compound (IV), compound (V), tetra-triphenylphosphine palladium and isopropyl acetate are stirred in there-necked flask
After mixing dissolving, vacuum switching nitrogen adds deoxidation aqueous potassium phosphate solution, is heated to 80 DEG C and reacts 6-8 hours, and reaction terminates cold
But divide liquid, water to be extracted 1 time with isopropyl acetate, merge organic phase and wash 2 times, sodium sulphate is dried, and is concentrated to give compound (VI)
Directly cast single step reaction；
The step (3) is that 100 DEG C are heated to after compound (VI), ammonium acetate, toluene stir in there-necked flask instead
Answer 6-8 hours.Reaction end is cooled to room temperature and adds ethyl acetate, washes 2 times, and sodium sulphate is dried, and concentration removes most of molten
Agent, adds petroleum ether, mashing, filtration drying to obtain intermediate (VII)；
The step (4) is that compound (VII) and ethanol are added in there-necked flask, is heated to 65 DEG C, and hydrochloric acid is added dropwise,
Drip off rear insulation reaction 2 hours.Reaction is cooled to 45 DEG C after terminating, and adds a small amount of product crystal seed, and product starts slowly to separate out,
It is slowly cooled to room temperature after being incubated 1 hour after low temperature, filters, dries, obtaining compound (VIII)；
The step (5) is that compound (VIII), EDCI, HOBt, Moc-L- valine and N,N-dimethylformamide exist
Stirring and dissolving in there-necked flask.Room temperature is slowly added dropwise N-methylmorpholine, drips off latter room temperature reaction 6-8 hours.Reaction adds after terminating
Enter isopropyl acetate and water, point liquid, organic phase is successively washed with water, and sodium acid carbonate is washed, washing is dried, and is concentrated to give grease
Lei Dipawei crude products.Grease Lei Dipawei crude products add acetone, are heated with stirring to 45 DEG C of dissolvings, add a small amount of Lei Dipawei third
Assimilation compound crystal seed, slow cooling, product is largely separated out.Slow cooling continues to stir 2 hours after being down to room temperature, filtering, filter
Cake is washed with a small amount of acetone, get Lei Dipawei acetonides after 45 DEG C of vacuum drying.
A of the present invention is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, and E is (S) -2- (methyloxycarbonylamino) -3-
During methylbutyraldehyd base, processing step is：
(1) compound of the compound of chemical formula (II) and chemical formula (III) reaction under alkali effect obtains chemical formula (IV)
Compound：
(2) compound of the compound of chemical formula (IV) and chemical formula (V) reaction under metallic catalyst effect obtains chemistry
The compound of formula (VI)：
(3) compound of chemical formula (VI) carries out the compound that ring-closure reaction obtains chemical formula (VII) with amine reagent：
(4) compound of chemical formula (VII) obtains the compound of chemical formula (VIII) under acid effect：
(5) compound of chemical formula (VIII) obtains the chemical combination of chemical formula (I) with Moc-L- valines under condensing agent effect
Thing.
The step (1) is that compound (II), compound (III), acetonitrile are stirring evenly and then adding into carbon in there-necked flask
Sour potassium, is heated to 50 DEG C and reacts 4-6 hour, and reaction terminates to add water, is cooled to room temperature mashing, filtering, washes, dry must change
Compound (IV)；
The step (2) is in there-necked flask by compound (IV), compound (V), tetra-triphenylphosphine palladium and isopropyl acetate
After middle stirring and dissolving, vacuum switching nitrogen adds deoxidation aqueous potassium phosphate solution, is heated to 80 DEG C and reacts 6-8 hours, reaction knot
Beam cooling point liquid, water is extracted 1 time with isopropyl acetate, is merged organic phase and is washed 2 times, and sodium sulphate is dried, and is concentrated to give chemical combination
Thing (VI), directly casts single step reaction；
The step (3) is to be heated to 100 DEG C after compound (VI), ammonium acetate and toluene stir in there-necked flask
Reaction 6-8 hours.Reaction end is cooled to room temperature and adds ethyl acetate, washes 2 times, and sodium sulphate is dried, and concentration removes most of
Solvent, adds petroleum ether, mashing, filtration drying to obtain compound (VII)；
The step (4) is that compound (VII), acetonitrile are added in there-necked flask, is heated to 65 DEG C, and hydrochloric acid is added dropwise,
Drip off rear insulation reaction 2 hours.Reaction is cooled to 45 DEG C after terminating, and is added dropwise to acetonitrile and adds a small amount of product crystal seed, product to start
Slowly separate out, 1 hour is incubated after dripping off.Continue to instill acetonitrile, drip off insulation 2 hours, be slowly cooled to room temperature, filter,
Solid is washed with acetonitrile, is dried, and obtains compound (VIII)；
The step (5) is that compound (VIII), EDCI, HOBt, Moc-L- valine and N,N-dimethylformamide exist
Stirring and dissolving is added in there-necked flask.Room temperature is slowly added dropwise N-methylmorpholine, drips off latter room temperature reaction 6-8 hours.Add water,
Room temperature reaction 6-8 hours.Reaction adds isopropyl acetate and water after terminating, and point liquid, organic phase is successively washed with water, bicarbonate
Sodium is washed, washing, is dried, and is concentrated to give grease Lei Dipawei crude products.Grease Lei Dipawei crude products add acetone, stir and add
Heat adds a small amount of Lei Dipawei acetonides crystal seed, slow cooling, product largely to separate out to 45 DEG C of dissolvings.Slow cooling drops
Continue to stir 2 hours after to room temperature, filtering, filter cake is washed with a small amount of acetone, get Lei Dipawei acetonations after 45 DEG C of vacuum drying
Compound.
A of the present invention is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, and E is (S) -2- (methyloxycarbonylamino) -3-
During methylbutyraldehyd base, processing step is：
(1) compound of the compound of chemical formula (II) and chemical formula (III) reaction under alkali effect obtains chemical formula (IV)
Compound：
(2) compound of the compound of chemical formula (IV) and chemical formula (V) reaction under metallic catalyst effect obtains chemistry
The compound of formula (VI)：
(3) change
The compound of formula (VI) carries out the compound that ring-closure reaction obtains chemical formula (I) with amine reagent：
The step (1) is that compound (I I), compound (I II), acetonitrile are stirring evenly and then adding into carbon in there-necked flask
Sour potassium, is heated to 50 DEG C and reacts 4-6 hours, and reaction terminates to add water, is cooled to room temperature mashing, and filtering, washing is dry to change
Compound (IV)；
The step (2) is in there-necked flask by compound (IV), compound (V), tetra-triphenylphosphine palladium and isopropyl acetate
After middle stirring and dissolving, vacuum switching nitrogen adds deoxidation aqueous potassium phosphate solution, is heated to 80 DEG C and reacts 6-8 hours, reaction knot
Beam cooling point liquid, water is extracted 1 time with isopropyl acetate, is merged organic phase and is washed 2 times, and sodium sulphate is dried, and is concentrated to give chemical combination
Thing (VI) directly casts single step reaction；
The step (3) is to add compound (VI) crude product, ammonium acetate, toluene to be heated to after stirring in there-necked flask
100 DEG C are reacted 6-8 hours.Reaction end is cooled to room temperature and adds ethyl acetate, washes 2 times, and sodium sulphate is dried, and concentration removes big
Partial solvent, obtains grease Lei Dipawei crude products.Grease Lei Dipawei crude products add acetone, and stirring and dissolving is simultaneously heated to 45 DEG C,
A small amount of Lei Dipawei acetonides crystal seed, slow cooling, product is added largely to separate out.Slow cooling continues to stir after being down to room temperature
Mix 2 hours, filtering, filter cake are washed with a small amount of acetone, get Lei Dipawei acetonides after 45 DEG C of vacuum drying.
The present invention has positive effect：Present invention process route is short, especially A, and B is (S) -2- (methyloxycarbonylamino) -3-
Easy to operate during methylbutyraldehyd base, reaction yield is high.
Specific embodiment
(embodiment 1)
By compound (II) (30.43g, 102mmol), compound (III) (35.76g, 100mmol), acetonitrile (360mL) is three
After being stirred in mouth flask, potassium carbonate (27.64g, 200mmol) is added, be heated to 50 DEG C and react 4-6 hours, reaction knot
Beam adds water (720mL), is cooled to room temperature mashing, filtering, washing, dry compound (IV) (59.47g, yield 96%).
By compound (IV) (59.47g, 96mmol), compound (V) (43.94g, 100mmol), tetra-triphenylphosphine palladium (3.32g,
2.88mmol) with isopropyl acetate (600mL) after there-necked flask stirring and dissolving, vacuum switching nitrogen adds deoxidation potassium phosphate water-soluble
Liquid (2.0mol/L, 300mL), is heated to 80 DEG C and reacts 6-8 hours, and reaction terminates cooling point liquid, and water mutually uses isopropyl acetate
(200mL) extract 1 time, merge organic phase wash 2 times (300mL), sodium sulphate dry, be concentrated to give compound (VI) (85g, slightly
Product 100%) directly cast single step reaction.
By compound (VI) (crude product 85g, 96mmol), ammonium acetate (37g, 480mmol), toluene (850mL) is in there-necked flask
In stir after be heated to 100 DEG C react 6-8 hours.Reaction end is cooled to room temperature and adds ethyl acetate (340mL), washing 2
Secondary (510mL), sodium sulphate is dried, and concentration removes most of solvent, adds petroleum ether (510mL), mashing, during filtration drying is obtained
Mesosome (VII) (54.3g, 2 step yields 68%).
Compound (VII) (54g, 64.9mmol) and ethanol 216mL are added in there-necked flask, 65 DEG C, drop are heated to
Plus 6mol/L hydrochloric acid (43mL, 130mmol), drip off rear insulation reaction 2 hours.Reaction is cooled to 45 DEG C after terminating, and adds few
Volume production product crystal seed, product starts slowly to separate out, and is slowly cooled to room temperature after being incubated 1 hour after low temperature, filters, and dries, and obtains
Compound (VIII) about 56g (crude product is aqueous, and yield is based on 100%).
By compound (VIII) (crude product 56g, 64.9mmol), EDCI (14.93g, 77.88mmol), HOBt (11.4g,
84.37mmol), Moc-L- valines (12.51g, 71.39mmol) and DMF (300mL) are in there-necked flask
Middle stirring and dissolving.Room temperature is slowly added dropwise N-methylmorpholine (21.33g, 210.92mmol), drips off latter room temperature reaction 6-8 hours.
Reaction adds 500mL isopropyl acetates and 500mL water after terminating, point liquid, and organic phase is successively washed with 250mL again, 250mL 5%
Sodium acid carbonate is washed, 250mL washings, is dried, and is concentrated to give grease Lei Dipawei crude products.
Grease Lei Dipawei crude products add acetone 750mL, are heated with stirring to 45 DEG C of dissolvings, add a small amount of Lei Dipawei acetonations
Compound crystal seed, slow cooling, product is largely separated out.Slow cooling continues to stir 2 hours after being down to room temperature, and filtering, filter cake is used
A small amount of acetone washing, get Lei Dipawei acetonides 48g after 45 DEG C of vacuum drying.
(embodiment 2)
By compound (II) (24.71g, 102mmol), compound (III) (35.76g, 100mmol), acetonitrile (360mL)
Potassium carbonate (27.64g, 200mmol) is stirring evenly and then adding into there-necked flask, 50 DEG C is heated to and is reacted 4-6 hours, reaction
Terminate to add water (720mL), be cooled to room temperature mashing, filtering, washing, dry compound (IV) (54.55g, yield 97%).
By compound (IV) (54.55g, 97mmol), compound (V) (44.39g, 101mmol), tetra-triphenylphosphine palladium (3.36g,
2.91mmol) with isopropyl acetate (55mL) after stirring and dissolving in there-necked flask, vacuum switching nitrogen adds deoxidation potassium phosphate
The aqueous solution (2.0mol/L, 300mL), is heated to 80 DEG C and reacts 6-8 hours, and reaction terminates cooling point liquid, and water is mutually different with acetic acid
Propyl ester (200mL) extract 1 time, merge organic phase wash 2 times (300mL), sodium sulphate dry, be concentrated to give compound (VI) (79.50g,
Crude yield 100%), directly cast single step reaction.
By compound (VI) (crude product 79.50g, 97mmol), ammonium acetate (37.38g, 485mmol) and toluene (795mL) are three
100 DEG C are heated to after being stirred in mouth flask to react 6-8 hours.Reaction end is cooled to room temperature and adds ethyl acetate (320mL),
2 times (480mL) of washing, sodium sulphate is dried, and concentration removes most of solvent, adds petroleum ether (480mL), and mashing is crossed and is filtered dry
It is dry to obtain compound (VII) (53.33g, two step yields 71%).
Compound (VII) (50g, 64.52mmol) is added in there-necked flask, acetonitrile 200mL is added, 65 DEG C are heated to,
2mol/L hydrochloric acid (161mL, 322mmol) is added dropwise, rear insulation reaction is dripped off 2 hours.Reaction is cooled to 45 DEG C after terminating, and is added dropwise to
Acetonitrile 200mL simultaneously adds a small amount of product crystal seed, and product starts slowly to separate out, and 1 hour is incubated after dripping off.Continue to instill acetonitrile 600mL,
Insulation 2 hours is dripped off, is slowly cooled to room temperature, filtered, solid is washed with acetonitrile 100mL, dried, obtain compound (VIII)
(crude product 48g is aqueous, and yield is based on 100%).
By compound (VIII) (48g, 64.52mmol), EDCI (29.68g, 154.82mmol), HOBt (22.66g,
167.73mmol), Moc-L- valines (24.86g, 141.92mmol) and DMF 480mL are in there-necked flask
Middle addition stirring and dissolving.Room temperature is slowly added dropwise N-methylmorpholine (42.41g, 419.32mmol), drips off rear room temperature reaction 6-8 small
When.Add 50mL water, room temperature reaction 6-8 hours.Reaction adds 450mL isopropyl acetates and 600mL water after terminating, point
Liquid, organic phase is successively washed with 450mL again, and the sodium acid carbonates of 450mL 5% are washed, 450mL washings, is dried, and is concentrated to give grease
Lei Dipawei crude products.
Grease Lei Dipawei crude products add acetone 670mL, are stirred and heated to 45 DEG C of dissolvings, add a small amount of Lei Dipawei acetone
Compound crystal seed, slow cooling, product is largely separated out.Slow cooling continues to stir 2 hours after being down to room temperature, filtering, filter cake
Washed with a small amount of acetone, get Lei Dipawei acetonides 46g after 45 DEG C of vacuum drying.
(embodiment 3)
By compound (II) (30.43g, 102mmol), compound (III) (35.76g, 100mmol), acetonitrile (360mL),
Potassium carbonate (27.64g, 200mmol) is stirring evenly and then adding into there-necked flask, 50 DEG C is heated to and is reacted 4-6 hours, reaction
Terminate to add water (720mL), be cooled to room temperature mashing, filtering, washing, dry compound (IV) (59.47g, yield 96%).
By compound (IV) (59.47g, 96mmol), compound (V) (49.64g, 100mmol), tetra-triphenylphosphine palladium (3.32g,
2.88mmol) with isopropyl acetate (600mL) after stirring and dissolving in there-necked flask, vacuum switching nitrogen adds deoxidation potassium phosphate
The aqueous solution (2.0mol/L, 300mL), is heated to 80 DEG C and reacts 6-8 hours, and reaction terminates cooling point liquid, and water is mutually different with acetic acid
Propyl ester (200mL) extract 1 time, merge organic phase wash 2 times (300mL), sodium sulphate dry, be concentrated to give compound (VI) (91g,
Crude product 100%) directly cast single step reaction.
Compound (VI) crude product (91g, 96mmol), ammonium acetate (37g, 480mmol), toluene (910 are added in there-necked flask
ML), 100 DEG C are heated to after stirring to react 6-8 hours.Reaction end is cooled to room temperature and adds ethyl acetate (364mL), water
Wash 2 times (546mL), sodium sulphate is dried, concentration removes most of solvent, obtains grease Lei Dipawei crude products about 70g.
Grease Lei Dipawei crude products add acetone 950mL, and stirring and dissolving is simultaneously heated to 45 DEG C, a small amount of Lei Dipawei acetone of addition
Compound crystal seed, slow cooling, product is largely separated out.Slow cooling continues to stir 2 hours after being down to room temperature, filtering, filter cake
Washed with a small amount of acetone, get Lei Dipawei acetonides 63g after 45 DEG C of vacuum drying.
Particular embodiments described above, is further described to the purpose of the present invention, technical scheme and beneficial effect,
Should be understood that and the foregoing is only specific embodiment of the invention, be not intended to limit the invention, it is all in the present invention
Spirit and principle within, any modification, equivalent substitution and improvements done etc., should be included in protection scope of the present invention it
It is interior.
Claims (12)
1. a kind of preparation method of Lei Dipawei, it is characterised in that：With following steps：The structural formula of Qi Zhong Suo Shu Lei Dipawei is
Chemical formula (I)
(1) compound of the compound of chemical formula (II) and chemical formula (III) reaction under alkali effect obtains chemical formula (IV)
Compound：
(2) compound of the compound of chemical formula (IV) and chemical formula (V) reaction under metallic catalyst effect obtains chemistry
The compound of formula (VI)：
(3) compound of chemical formula (VI) carries out the compound that ring-closure reaction obtains chemical formula (VII) with amine reagent：
(4) compound of chemical formula (VII) obtains the compound of chemical formula (VIII) under acid effect：
(5) compound of chemical formula (VIII) obtains the compound of chemical formula (I) with Moc-L- valines under condensing agent effect.
Wherein,
A, E, X, Y are defined as follows：
When A is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, E is tertbutyloxycarbonyl, then X is hydrogen, and Y is (S) -2- (first
Epoxide carbonyl amino) -3- methylbutyraldehyd bases, n is 3；Or
When A is tertbutyloxycarbonyl, E is tertbutyloxycarbonyl, then X is hydrogen, and Y is hydrogen, and n is 4；Or
When A is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, E is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases,
Then X is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, and Y is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, n
It is 0.
2. the preparation method of Lei Dipawei according to claim 1, it is characterised in that：In the step (1), alkali used is
Potassium carbonate, solvent for use is acetonitrile.
3. the preparation method of Lei Dipawei according to claim 1, it is characterised in that：In the step (2), metal used
Catalyst is tetra-triphenylphosphine palladium, and solvent for use is isopropyl acetate.
4. the preparation method of Lei Dipawei according to claim 1, it is characterised in that：In the step (3), amine examination used
Agent is Ammoniom-Acetate, and solvent for use is toluene.
5. the preparation method of Lei Dipawei according to claim 1, it is characterised in that：In the step (4), institute
It is hydrochloric acid with acid, solvent for use is ethanol or acetonitrile.
6. the preparation method of Lei Dipawei according to claim 1, it is characterised in that：In the step (5), condensation used
Agent is HOBt and EDCI, and solvent for use is DMF and N-methylmorpholine.
7. the preparation method of Lei Dipawei according to claim 1, it is characterised in that：When A is (S) -2- (methoxycarbonyl ammonia
Base) -3- methylbutyraldehyd bases, when E is tertbutyloxycarbonyl, preparation process is：
(1) compound of the compound of chemical formula (II) and chemical formula (III) reaction under alkali effect obtains chemical formula (IV)
Compound：
(2) compound of the compound of chemical formula (IV) and chemical formula (V) reaction under metallic catalyst effect obtains chemical formula (VI)
Compound：
(3) compound of chemical formula (VI) carries out the compound that ring-closure reaction obtains chemical formula (VII) with amine reagent：
(4) compound of chemical formula (VII) obtains the compound of chemical formula (VIII) under acid effect：
(5) compound of chemical formula (VIII) obtains the chemical combination of chemical formula (I) with Moc-L- valines under condensing agent effect
Thing.
8. the preparation method of the Lei Dipawei described in claim 7, it is characterised in that：
The step (1) is after compound (II), compound (III), acetonitrile stir in reaction bulb, to add carbonic acid
Potassium, is heated to 50 DEG C and reacts 4-6 hour, and reaction terminates to add water, is cooled to room temperature mashing, filtering, wash, dry chemical combination
Thing (IV)；
The step (2) is that compound (IV), compound (V), tetra-triphenylphosphine palladium and isopropyl acetate are stirred in reaction bulb
After mixing dissolving, deoxidation aqueous potassium phosphate solution is added, be heated to 80 DEG C and react 6-8 hour, reaction terminates a cooling point liquid, through extracting,
Wash, dry, be concentrated to give compound (VI)；
The step (3) is that 100 DEG C of reactions are heated to after compound (VI), ammonium acetate, toluene stir in reaction bulb
6-8 hours, reaction end was cooled to room temperature and adds ethyl acetate, washes, dries, and concentration removes most of solvent, addition oil
Ether, mashing, filtration drying obtain intermediate (VII)；
The step (4) is that compound (VII) and ethanol are added in reaction bulb, is heated to 65 DEG C, and hydrochloric acid is added dropwise, and is protected
Temperature reaction 2 hours, reaction is cooled to 45 DEG C after terminating, through separating out, filtering, dry, obtain compound (VIII)；
The step (5) is that compound (VIII), EDCI, HOBt, Moc-L- valine and N,N-dimethylformamide exist
Stirring and dissolving in reaction bulb, room temperature is slowly added dropwise N-methylmorpholine, drips off latter room temperature reaction 6-8 hours, and reaction is added after terminating
Isopropyl acetate and water, point liquid, organic phase are successively washed with water, and sodium acid carbonate is washed, washing, are dried, and are concentrated to give grease thunder
Di Pawei crude products, treated rear get Lei Dipawei acetonides.
9. the preparation method of Lei Dipawei according to claim 1, it is characterised in that：It is described when A is (S) -2- (methoxyl groups
Carbonylamino) -3- methylbutyraldehyd bases, when E is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, preparation process is：
(1) compound of the compound of chemical formula (II) and chemical formula (III) reaction under alkali effect obtains chemical formula (IV)
Compound：
(2) compound of the compound of chemical formula (IV) and chemical formula (V) reaction under metallic catalyst effect obtains chemistry
The compound of formula (VI)：
(3) compound of chemical formula (VI) carries out the compound that ring-closure reaction obtains chemical formula (VII) with amine reagent：
(4) compound of chemical formula (VII) obtains the compound of chemical formula (VIII) under acid effect：
(5) compound of chemical formula (VIII) obtains the chemical combination of chemical formula (I) with Moc-L- valines under condensing agent effect
Thing.
10. the preparation method of the Lei Dipawei described in claim 9, it is characterised in that：
The step (1) is that compound (II), compound (III), acetonitrile are stirring evenly and then adding into carbonic acid in reaction bulb
Potassium, is heated to 50 DEG C and reacts 4-6 hour, and reaction terminates to add water, is cooled to room temperature mashing, filtering, wash, dry chemical combination
Thing (IV)；
The step (2) be by compound (IV), compound (V), tetra-triphenylphosphine palladium and isopropyl acetate in reaction bulb
After stirring and dissolving, deoxidation aqueous potassium phosphate solution is added, be heated to 80 DEG C and react 6-8 hours, reaction terminates cooling point liquid, through extraction
Take, wash, drying, being concentrated to give compound (VI)；
The step (3) is that 100 DEG C are heated to after compound (VI), ammonium acetate and toluene stir in reaction bulb instead
Answer 6-8 hours, reaction end is cooled to room temperature and adds ethyl acetate, washes, dries, concentration removes most of solvent, addition stone
Oily ether, mashing, filtration drying obtain compound (VII)；
The step (4) is heated to 65 DEG C to add compound (VII), acetonitrile in reaction bulb, and hydrochloric acid is added dropwise, and drips off
Insulation reaction 2 hours, to react and be cooled to 45 DEG C after terminating afterwards, through separating out, filtering, dry, obtain compound (VIII)；
The step (5) is that compound (VIII), EDCI, HOBt, Moc-L- valine and N,N-dimethylformamide exist
Add stirring and dissolving, room temperature to be slowly added dropwise N-methylmorpholine in reaction bulb, drip off latter room temperature reaction 6-8 hours, add water,
Room temperature reaction 6-8 hours, reaction added isopropyl acetate and water after terminating, point liquid, and organic phase is successively washed with water, bicarbonate
Sodium is washed, washed, drying, and is concentrated to give grease Lei Dipawei crude products, treated rear get Lei Dipawei acetonides.
The preparation method of 11. Lei Dipawei according to claim 1, it is characterised in that：When A is (S) -2- (methyloxycarbonylamino) -3-
Methylbutyraldehyd base, when E is (S) -2- (methyloxycarbonylamino) -3- methylbutyraldehyd bases, preparation process is：
(1) compound of the compound of chemical formula (II) and chemical formula (III) reaction under alkali effect obtains chemical formula (IV)
Compound：
(2) compound of the compound of chemical formula (IV) and chemical formula (V) reaction under metallic catalyst effect obtains chemistry
The compound of formula (VI)：
(3) compound of chemical formula (VI) carries out the compound that ring-closure reaction obtains chemical formula (I) with amine reagent：
The preparation method of 12. Lei Dipawei according to claim 11, it is characterised in that：
The step (1) is, by compound (II), compound (III), acetonitrile, carbon to be stirring evenly and then adding into reaction bulb
Sour potassium, is heated to 50 DEG C and reacts 4-6 hour, and reaction terminates to add water, is cooled to room temperature mashing, filtering, washes, dry must change
Compound (IV)；
The step (2) is that tetra-triphenylphosphine palladium and isopropyl acetate are in reaction bulb by compound (IV), compound (V)
After stirring and dissolving, deoxidation aqueous potassium phosphate solution is added, be heated to 80 DEG C and react 6-8 hour, reaction terminates a cooling point liquid, through extracting,
Wash, dry, be concentrated to give compound (VI；
The step (3) is that compound (VI) crude product, ammonium acetate, toluene will be added to be heated to after stirring in reaction bulb
100 DEG C are reacted 6-8 hours, and reaction end is cooled to room temperature and adds ethyl acetate, washing, sodium sulphate to dry, and concentration removes most of
Solvent, obtains grease Lei Dipawei crude products, the treated rear get Lei Dipawei acetonides of grease Lei Dipawei crude products.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107987125A (en) * | 2017-11-23 | 2018-05-04 | 爱斯特（成都）生物制药股份有限公司 | A kind of preparation method of valine derivative |
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Application publication date: 20170627 |