CN106256825A - The synthetic method of his Wei of Dacca - Google Patents
The synthetic method of his Wei of Dacca Download PDFInfo
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- CN106256825A CN106256825A CN201610514083.5A CN201610514083A CN106256825A CN 106256825 A CN106256825 A CN 106256825A CN 201610514083 A CN201610514083 A CN 201610514083A CN 106256825 A CN106256825 A CN 106256825A
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- C07—ORGANIC CHEMISTRY
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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 provides the synthetic method of his Wei of a kind of Dacca; it includes with 4; 4 ' two (2 haloacetyl) biphenyl is raw material, with N (methoxycarbonyl group) L valine L proline, esterification occurs in the presence of organic solvent and alkali, obtains intermediate B.Then, intermediate B and ammonium acetate occur cyclodehydration to react in xylene solution at 100 120 DEG C and obtain free alkali C.Subsequently, after free alkali C with HCl reacts, obtain his Wei crude product of Dacca.Finally, his Wei of Dacca is obtained after his Wei crude product recrystallization of Dacca.This synthetic method, has advantages such as synthetic route is simple and convenient to operate, purification is simple, and high through he Wei Chundu of Dacca that this synthetic reaction obtains, yield is big, greatly improve the quality of his Wei crude drug of Dacca, reduce its production cost, be suitable for industrialized great production.
Description
Technical field
The present invention relates to chemical medicine field, in particular to the synthetic method of his Wei of a kind of Dacca.
Background technology
Hepatitis C is the abbreviation of hepatitis C, is that a kind of inflammation caused by hepatitis C virus (HCV) is downright bad
Infectious disease, very harmful to the health and lives of people.His Wei (Daclatasvir) of Dacca is to be researched and developed by Bristol-Myers Squibb Co.
One anti-hepatitis C virus medicine, this medicine associating Suo Feibuwei (Sofosbuvir) treatment is without the gene 3 type hepatitis C patient of liver cirrhosis
In, cure rate is up to 97%.Its structure is as follows:
At present, his method of Wei of synthesis Dacca mainly has:
Method one, patent WO2009020825 reports the synthetic method such as Fig. 2. the method by bromo, be esterified, become
Ring, deprotection, formation peptide bond, finally become salt 6 steps of purification.According to the report of this patent, this synthesis technique complex steps,
Especially at ring-forming sequence, post processing needs to carry out at a certain temperature washing impurity separatory, and this operation is very difficult to behaviour
Control.And during separatory, have solvent toluene volatilization, health is brought harm.Additionally, deprotection obtains in the middle of four salt
Body, in order to preferably control its quality, needs to be purified process；But the dissolubility of this four salt intermediate is the poorest, all
Organic solvent the most excessively poor to its dissolubility, cause purification difficult.
Method two, document Nature, Vol465, P.96-100 report the synthesis technique such as Fig. 3, the method is with 4-bromobenzene
Ethyl ketone is raw material, by bromo, esterification, cyclization, Suzuki coupling, deprotection, connects peptide, becomes salt etc. seven steps reaction to obtain target to produce
Thing.This technique not only synthetic route is long, and has a step Suzuki coupling reaction in building-up process, and this reaction not only to be used high
Expensive palladium or other palladium make catalyst, and reaction needs the oxygen free condition that nitrogen is protected.This not only increases reaction
Cost, also operates also inconvenient, is unfavorable for producing greatly.According to the literature, the purification process of this product is with the side of column chromatography to root
Method, it is clear that be unfavorable for industrialized production.
Method three, patent WO2012048421 reports the synthetic method such as Fig. 4.Obviously the synthetic method of Fig. 4 is with Fig. 3's
Synthetic method is similar.It is all with 4-bromoacetophenone as raw material, will be through Suzuki coupling reaction.Its defect is aobvious and easy
See, be unfavorable for industrialized production.
No matter the technique that presently, there are, be with 4-bromoacetophenone as raw material, or is former with 4,4 '-diacetyl biphenyl
, all there is the unfavorable factors such as process route length, complex operation, severe reaction conditions, use metallic catalyst in material.These are disadvantageous
Factor directly affects quality and the cost thereof of crude drug.
Summary of the invention
It is an object of the invention to provide the synthetic method of his Wei of a kind of Dacca, this synthetic method and the synthesis side reported
Method is compared, and has advantages such as synthetic route is simple and convenient to operate, purification is simple, and through his Wei of Dacca that this synthetic reaction obtains
Purity is high, and yield is big, greatly improves the quality of his Wei crude drug of Dacca, reduces its production cost, be suitable for industrialization big
Produce.
In order to realize the above-mentioned purpose of the present invention, spy by the following technical solutions:
The synthetic method of his Wei of a kind of Dacca, comprises the following steps:
Step a: with 4,4 '-two (2-haloacetyl) biphenyl for raw material, with N-(methoxycarbonyl group)-Valine-L-dried meat
There is esterification in propylhomoserin in the presence of organic solvent and alkali, obtains intermediate B；
Step b: intermediate B and ammonium acetate occur cyclodehydration to react and obtain in xylene solution at 100-120 DEG C
Free alkali C；
Step c: after free alkali C with HCl reacts, obtains his Wei crude product of Dacca；
Step d: obtain his Wei of Dacca after his Wei crude product recrystallization of Dacca；
Reaction scheme is as follows:
Wherein, X is Cl, Br or I.
Compared with prior art, the invention have the benefit that
(1) present invention with 4,4 '-two (2-haloacetyl) biphenyl (compound A) for raw material, only by esterification and
Cyclodehydration reacts, and i.e. obtains the free alkali of his Wei of free alkali C, i.e. Dacca.Free alkali C carries out into salt again, the most i.e. obtains
His Wei of highly purified Dacca.Synthesis technique is simple, be prone to purification, and synthesis cycle is short, application is strong.
(2) in step b of this synthetic method, employing dimethylbenzene is reaction dissolvent, and is dehydrated at 100-120 DEG C
Condensation reaction, it is possible to the effective yield improving free alkali C, this has most important for the obtained quantity of his Wei of end-product Dacca
Meaning.This just imply that, in the industrial production, produces his Wei of Dacca of same quality, uses the present processes can pole
Big saving production cost.
(3) in step d of this synthetic method, after recrystallization, the purity of his Wei of gained Dacca is more than 99.5%, and single
One impurity is less than 0.1%, and his Wei of gained Dacca detects through X-ray powder diffraction, it was demonstrated that its crystal formation is Form N-2 crystal formation.
(4), in this synthetic method, whole technique is without reference to the relatively harsh reaction of the conditions such as anhydrous, anaerobic, and does not has
Use the heavy metal toxic reagent such as palladium etc, environmentally friendly, and be conducive to controlling in Dacca his Wei crude drug miscellaneous
Matter and the amount of heavy metal, obtain his Wei crude drug of highly purified Dacca, with low cost, is suitable for that industry is big to be produced.
Accompanying drawing explanation
In order to be illustrated more clearly that the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing
In having technology to describe, the required accompanying drawing used is briefly described.
The synthetic route of his Wei of Dacca that Fig. 1 provides for the present invention；
Fig. 2 is the synthetic route of his Wei of Dacca disclosed in patent WO2009020825；
Fig. 3 is the synthetic route of his Wei of the Dacca disclosed in Nature periodical；
Fig. 4 is the synthetic route of his Wei of Dacca disclosed in patent WO2012048421.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but those skilled in the art will
Understanding, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the present invention.In embodiment unreceipted specifically
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or instrument unreceipted production firm person, be
Can be by the commercially available conventional products bought and obtain.
The synthetic method of his Wei of a kind of Dacca that present embodiment provides, reaction scheme is as follows:
Wherein, X is Cl, Br or I.
This synthetic method comprises the following steps:
Step a: with 4,4 '-two (2-haloacetyl) biphenyl for raw material, with N-(methoxycarbonyl group)-Valine-L-dried meat
There is esterification in propylhomoserin (Moc-Val-Pro) in the presence of organic solvent and alkali, obtains intermediate B.
In preferred embodiment of the present invention, above-mentioned 4,4 '-two (2-haloacetyl) biphenyl is by 4,4 '-diacetyl
Biphenyl is prepared by halogenating reaction.4, the low price of 4 '-diacetyl biphenyl, it is readily obtained, by this halogenating reaction
Preparation 4,4 '-two (2-haloacetyl) biphenyl, can reduce the production cost of his Wei crude drug of Dacca greatly.
In preferred embodiment of the present invention, the halogen atom in above-mentioned halogenating reaction is Cl, Br or I, this halogen atom
It is preferably Br.Further, when carrying out bromo-reaction, brominated reagent used is selected from bromine, N-bromosuccinimide
(NBS), pyridinium tribromide, bromination ketone etc., preferentially select bromine.While making bromo-reaction be smoothed out, by-product is few, institute
With the preferential selection 2.0-2.02eq of the consumption of bromine.
In preferred embodiment of the present invention, used molten in the reaction of synthesis 4,4 '-two (2-haloacetyl) biphenyl
Agent is selected from as acetic acid, dichloromethane, chloroform, oxolane or 2-methyltetrahydrofuran.Solvent made by preferential selection acetic acid.Should
The temperature of reaction controls in the range of 30-40 DEG C.By the control of these conditions, by the compound A of this halogenating reaction gained
Yield big, and impurity is few.
In preferred embodiment of the present invention, the halogen element in above-mentioned 4,4 '-two (2-haloacetyl) biphenyl is bromine.
4,4 '-two (2-Bromoacetyl) biphenyl as raw material, advantageously his Wei crude drug in the Dacca of synthesis of high purity.
In preferred embodiment of the present invention, above-mentioned alkali selected from triethylamine, DIPEA, the ammonia of 25% or
One in the dimethylamine agueous solution of 20%.Above-mentioned alkali is preferably N, N-diisopropylethylamine.It is further preferred that control reaction
The pH of liquid is 8-9, and reaction temperature is 25-30 DEG C.By the control of these conditions, by the intermediate B of this esterification gained
Yield big, and impurity is few.
In preferred embodiment of the present invention, the reaction dissolvent of above-mentioned esterification is selected from oxolane, N, N-dimethyl
One in Methanamide, dimethyl sulfoxide or acetonitrile；Prioritizing selection acetonitrile.These reaction dissolvents be advantageously selected for improve intermediate
The yield of B.
In preferred embodiment of the present invention, the consumption of above-mentioned Moc-Val-Pro is the 2-3 equivalent of compound A, is preferably
2.5 equivalent.Such dosage, is conducive to making this esterification fully complete, improves the yield of intermediate B further.
Step b: intermediate B and ammonium acetate occur cyclodehydration to react and obtain in xylene solution at 100-120 DEG C
Free alkali C.
Employing dimethylbenzene is reaction dissolvent, and dehydration condensation occurs at 100-120 DEG C.Solvent due to dimethylbenzene
Property good, for toluene, dimethylbenzene and water can be easily formed azeotropic mixture, so that the water of generation is continuous in Fan Ying
Reducing, be conducive to reaction to move towards the direction generating free alkali C, effectively raise the yield of free alkali C, this is for whole product
The obtained quantity of his Wei of thing Dacca has vital meaning.This just imply that, in the industrial production, produces reaching of same quality
Mucositis Wei, uses the present processes can greatly save production cost.
In preferred embodiment of the present invention, during carrying out cyclodehydration reaction, constantly remove in reactant liquor raw
The water become, makes in reactant liquor water content control below 0.05%.Wherein, water content can characterize by karl Fischer value.No
The water produced in disconnected removing reaction, is conducive to making this cyclodehydration molecular balance move, favorably towards the direction generating free alkali C
In adding the carrying out of fast response, improve the yield of free alkali C simultaneously.
In present invention embodiment preferably, controlling the pH of reactant liquor in the reaction of this cyclodehydration is 4-5.In the present invention
In embodiment preferably, the consumption of solvent for use diphenylamines is 16-17 times of the quality of intermediate B.On it is further preferred that
State that the consumption of ammonium acetate is the quality of intermediate B 1.9-2.3 times.The optimization of these conditions, is conducive to improving further dissociating
The yield of alkali C and purity.
Step c: after free alkali C with HCl reacts, obtains his Wei crude product of Dacca.
In present invention embodiment preferably, the reaction dissolvent of above-mentioned reaction is selected from ethanol, isopropanol, acetone, acetic acid
At least one in ethyl ester, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane or 2-methyltetrahydrofuran.Reaction dissolvent is preferential
Select ethanol.Be conducive to making free alkali C reaction completely, with the amount of his Wei crude product of Dacca obtained by improving.
In present invention embodiment preferably, above-mentioned HCl is hydrogen chloride gas or hydrogen chloride solution gas and methanol
Mixed solution or the mixed solution of the mixed solution of hydrogen chloride gas and ethanol or hydrogen chloride gas and ethyl acetate,
Or hydrogen chloride gas and the mixed solution of dioxane.More preferably, above-mentioned HCl is the ethanolic hydrogen chloride of 15-20%
Solution.May advantageously facilitate free alkali C and quickly react generation salt with HCl, and improve the yield of his Wei crude product of Dacca.
Step d: obtain his Wei of Dacca after his Wei crude product recrystallization of Dacca.
The purity of his Wei of gained Dacca is more than 99.5%, and single contaminant is less than 0.1%.His Wei of gained Dacca is through X-ray
Powder diffraction detects, it was demonstrated that its crystal formation is Form N-2 crystal formation.
In present invention embodiment preferably, recrystallization solution adds his Wei Chunpin of Dacca as crystal seed, crystal seed
It is 1:100-1000 with the mass ratio of his Wei crude product of Dacca.Herein, he Wei Chunpin of Dacca is that purity is more than 99% and single contaminant
The content his Wei of Dacca less than 0.1%.Add crystal seed, accelerate the crystallization of Dacca his Wei, and be avoided that his Wei of Dacca
With the impurity in solution for nucleus crystalline growth, be conducive to improving the purity of his Wei of Dacca.
In present invention embodiment preferably, the solution temperature of recrystallization is 15-45 DEG C.Be conducive to avoiding impurity at height
The lower structure of temperature changes, and affects purity and the yield of his Wei of Dacca.
In present invention embodiment preferably, selecting solvent during recrystallization is methanol, ethanol, acetone, diisopropyl ether, methyl
One or more in tertbutyl ether or ethyl acetate.Preferential selection methanol and the mixed solvent of acetone.Easily separate out crystal, and pure
Degree height.
The synthesis of embodiment 1 intermediate B and purification
By the 4 of 10kg, 4 '-two (2-Bromoacetyl) biphenyl, it is suspended in 78kg acetonitrile, adds the Moc-of 17.2kg
The DIPEA (DIPEA) of Val-Pro and 8.15kg, keeps temperature 20-25 degree reaction 24h.
After HPLC monitoring reaction completely, add 40kg water and 30kg ethyl acetate to reactant liquor.Stirring, isolates organic
Phase.Then by the 6mol/L salt acid elution organic facies of 30-40kg once, then organic facies is washed with 25kg 10% sodium carbonate liquor
Once, the NaCl solution followed in turn by 10% washs organic facies once.Finally, it is dried organic facies with 10kg anhydrous slufuric acid, filters
Rear removing solvent, obtains white solid 19.25kg.The yield of intermediate B is 98%, detects through HPLC, and its purity is 98.5%.
Intermediate B1H NMR(400MHz,DMSO-d6): δ 8.10 (d, J=12Hz, 4H), δ 7.96 (d, J=12Hz,
4H), δ 7.42 (d, J=8Hz, 2H), δ 5.65 (d, J=16,2H), δ 5.51 (d, J=20Hz, 2H), δ 5.48-5.67 (m,
2H),δ4.01-4.05(m,2H),δ3.81-3.83(m,2H),δ3.64-3.67(m,2H),δ3.53(s,6H),δ2.26-2.30
(m,2H),δ2.14-2.19(m,2H),δ1.90-2.02(m,8H),δ0.88-0.92(m,12H)。
The synthesis of embodiment 2 free alkali C and purification
By the dimethylbenzene of 335kg, the intermediate B of 19.5kg and the acetic acid of 38.5kg in the reactor have division box
Ammonium mixes, and makes the pH of reactant liquor between 4-5.Subsequently, under nitrogen protection, being heated to 100 DEG C enables reactant liquor to reflux.?
Reaction constantly removes, with water knockout drum, the water that reaction generates while carrying out, and reacts 3 hours, the karl Fischer value of detection reactant liquor,
Controlled in 0.05%.
After HPLC monitoring reaction completely, after reacting liquid temperature is down to 30-35 DEG C, it is slowly added in reactor
The sodium bicarbonate solution of 500kg 10% and the ethyl acetate of 300kg, after stirring mixing, isolate organic facies.Then, use
200kg citric acid regulation organic facies pH to 3-4, make gained free alkali C become salt and soluble in water in.Subsequently, organic
Adding isopyknic water in mutually, after mixing, isolate aqueous phase, now free alkali C is present in aqueous phase in a salt form；The most right
After, with the ethyl acetate of 100kg wash aqueous phase once after, in aqueous phase, add the ethyl acetate of 200kg, with 100kg 10% carbon
Acid sodium solution adjusts pH to 7-8, isolates organic facies, is designated as the first organic facies, now free alkali C presented in alkali in organic
Xiang Zhong；In order to improve the yield of free alkali C, then by 100kg ethyl acetate aqueous phase extracted once, isolate organic facies, be designated as
Two organic faciess.First organic facies and Second Organic Phase are merged, washed once by the NaCl solution of 100kg 10%, then with anhydrous
Sodium sulfate is dried, and removes solvent, obtain clear yellow viscous solid 18.4kg, yield 98.5% after filtration.Through the free C of HPLC detection
Purity be: 98.5%.
Free alkali C's1H NMR(400MHz,DMSO-d6): δ 11.78-12.21 (b, 2H), δ 7.26-7.79 (m, 12H), δ
5.09(s,2H),δ4.05-4.09(m,2H),δ3.81-3.83(m,2H),δ3.54(s,6H),δ2.02-2.15(m,4H),δ
1.95-1.96(m,6H),δ0.85-0.92(m,12H)。
The synthesis of embodiment 3 free alkali C and purification
By the dimethylbenzene of 335kg, the intermediate B of 19.5kg and the acetic acid of 38.5kg in the reactor have division box
Ammonium mixes, and makes the pH of reactant liquor between 4-5.Under nitrogen protection, being heated to 120 DEG C enables reactant liquor to reflux.In reaction
Constantly remove, with water knockout drum, the water that reaction generates while carrying out, react 3 hours.The karl Fischer value of detection reactant liquor, by it
Control in 0.01%.
In this embodiment, the purification process of free alkali C is same as in Example 2, and the clear yellow viscous solid of last gained is
18.2kg, yield 98.4%, the purity detecting free C through HPLC is: 98.6%.
The synthesis of embodiment 4 free alkali C and purification
By the dimethylbenzene of 335kg, the intermediate B of 19.5kg and the acetic acid of 38.5kg in the reactor have division box
Ammonium mixes, and makes the pH of reactant liquor between 4-5.Under nitrogen protection, being heated to 110 DEG C enables reactant liquor to reflux.In reaction
Constantly remove, with water knockout drum, the water that reaction generates while carrying out, react 3 hours.The karl Fischer value of detection reactant liquor, by it
Control in 0.001%.
In this embodiment, the purification process of free alkali C is same as in Example 2, and the clear yellow viscous solid of last gained is
18.6kg, yield 98.7%, the purity detecting free C through HPLC is: 98.5%.
The synthesis of embodiment 5 free alkali C and purification
In a kettle. the ammonium acetate of the dimethylbenzene of 335kg, the intermediate B of 19.5kg and 38.5kg is mixed, make reaction
The pH of liquid is between 4-5.Under nitrogen protection, it is heated to 110 DEG C and enables reactant liquor to reflux, react 3 hours.
In this embodiment, the purification process of free alkali C is same as in Example 2, and the clear yellow viscous solid of last gained is
16.9kg, yield 60.4%, the purity detecting free C through HPLC is: 95%.
The synthesis of his Wei crude product of embodiment 6 Dacca and purification
In a kettle., the ethanol that the free alkali C of 18kg is dissolved in 42kg, it is warming up to 45 DEG C.And make reactant liquor keep
At 45 DEG C, the ethanol solution of hydrogen chloride of the 20% of 2.2 equivalents is slowly added to above-mentioned reactant liquor.And at 45 DEG C, react 2.5
After hour, the temperature of reactant liquor is down to 25 DEG C, and reaction 12 hours at such a temperature.
Reacting liquid filtering, filter cake with 5kg alcohol flushing once, is dried and to obtain faint yellow solid 15.8kg, is his Wei of Dacca
Crude product, yield is 80.6%.The purity detecting his Wei crude product of Dacca through HPLC is: 98.5%, single miscellaneous in his Wei crude product of Dacca
The content of matter: 0.2%.
The synthesis of his Wei crude product of embodiment 7 Dacca and purification
In a kettle., the ethanol that the free alkali C of 18kg is dissolved in 42kg, it is warming up to 40.And make reactant liquor be maintained at
At 40 DEG C, the ethanol solution of hydrogen chloride of the 20% of 2.2 equivalents is slowly added to above-mentioned reactant liquor.And react 3 hours at 40 DEG C
After, the temperature of reactant liquor is down to 20 DEG C, and reaction 12 hours at such a temperature.
Reacting liquid filtering, filter cake with 5kg alcohol flushing once, is dried and to obtain faint yellow solid 15.8kg, is his Wei of Dacca
Crude product, yield is 80.2%.The purity detecting his Wei crude product of Dacca through HPLC is: 98.3%, single miscellaneous in his Wei crude product of Dacca
The content of matter: 0.3%.
The recrystallization of his Wei crude product of embodiment 8 Dacca
His Wei crude product of the Dacca of 10kg is dissolved in the methanol of 40kg, makes solution clarify at 25 DEG C, add the different of 40kg
Propanol, is subsequently added his Wei Chunpin of Dacca of 100g as crystal seed.It is slowly added in the acetone of 40kg while stirring, stirring
Crystallize 20h, sucking filtration, obtain 8.7kg off-white color solid, yield: 87.1%, through HPLC detection purity be: 99.6%, single contaminant is little
In 0.1%.
1H NMR(400MHz,DMSO-d6),δ14.8-15.2(b,4H),δ7.94-8.17(m,10H),δ7.30-7.37
(m,2H),δ5.19-5.21(b,2H),δ4.11-4.15(m,2H),δ4.00-4.06(m,2H),δ3.85(s,6H),δ2.19-
2.40(m,2H),δ1.91-2.01(m,8H),δ0.77-0.85(m,12H).
His Wei of Dacca detects through XRD, it was demonstrated that crystal formation is Form N-2 crystal formation, and its XRD data are as shown in table 1:
The XRD data of his Wei of table 1 Dacca
The recrystallization of his Wei crude product of embodiment 9 Dacca
His Wei crude product of the Dacca of 10kg is dissolved in the methanol of 40kg, makes solution clarify at 15 DEG C, add the different of 40kg
Propanol, is subsequently added his Wei Chunpin of Dacca of 10g as crystal seed.It is slowly added in the acetone of 40kg while stirring, stirring
Crystallize 15h, sucking filtration, obtain 8.8kg off-white color solid, be his Wei of Dacca, yield: 87.4%, through HPLC detection purity be:
99.7%, single contaminant is less than 0.1%.1H NMR data and XRD data are same as in Example 7.
The synthesis of embodiment 10 4,4 '-two (2-Bromoacetyl) biphenyl
By the 4 of 20kg, 4 '-diacetyl biphenyl is suspended in 400kg acetic acid, is warming up to 30 DEG C.Add 27.2kg's
Bromine, reacts 16h at 30-35 DEG C.
After HPLC monitoring reaction completely, filtering, the chloroform of filter cake 6kg rinses, and dries, obtains off-white powder 31kg.Will
The crude product 130kg oxolane recrystallization obtained, obtains off-white powder 25.1kg, yield: 75.6%, HPLC:98.4%.1H
NMR(400MHz,CDCl3)δ7.96-7.87(m,4H),δ7.51-7.62(m,4H),δ4.25(s,4H).
The synthesis of reference examples 1 free alkali C and purification
By the toluene of 335kg, the intermediate B of 19.5kg and the ammonium acetate of 38.5kg in the reactor have division box
Mixing, makes the pH of reactant liquor between 4-5.Under nitrogen protection, being heated to 100 DEG C enables reactant liquor to reflux.React into
Constantly remove, with water knockout drum, the water that reaction generates while row, react 3 hours.
In this reference examples, the purification process of free alkali C is same as in Example 2, and the clear yellow viscous solid of last gained is
14.5kg, yield 78.2%, the purity detecting free C through HPLC is: 97.8%.
The synthesis of reference examples 2 free alkali C and purification
By the toluene of 500g, the methanol of 500g, the intermediate B of 500g and 1kg in the reactor have division box
Ammonium acetate mixes, and makes the pH of reactant liquor between 4-5.Under nitrogen protection, being heated to 100 DEG C enables reactant liquor to reflux.?
Reaction constantly removes, with water knockout drum, the water that reaction generates while carrying out, and reacts 3 hours.
In this reference examples, the purification process of free alkali C is same as in Example 2, and the clear yellow viscous solid of last gained is
290g, yield 61.2%, the purity detecting free C through HPLC is: 92.3%.
The synthesis of reference examples 3 free alkali C and purification
By the dimethylbenzene of 335kg, the intermediate B of 19.5kg and the acetic acid of 38.5kg in the reactor have division box
Ammonium mixes, and makes the pH of reactant liquor between 5-6.Under nitrogen protection, 95 DEG C it are heated to.Constantly with dividing while reaction is carried out
Hydrophone removes the water that reaction generates, and reacts 3 hours.
In this reference examples, the purification process of free alkali C is same as in Example 2, and the clear yellow viscous solid of last gained is
14.5kg, yield 78.6%, the purity detecting free C through HPLC is: 96.1%.
The synthesis of reference examples 4 free alkali C and purification
By the dimethylbenzene of 335kg, the intermediate B of 19.5kg and the acetic acid of 38.5kg in the reactor have division box
Ammonium mixes, and makes the pH of reactant liquor between 4-5.Under nitrogen protection, being heated to 125 DEG C enables reactant liquor to reflux.In reaction
Constantly remove, with water knockout drum, the water that reaction generates while carrying out, react 3 hours.
In this reference examples, the purification process of free alkali C is same as in Example 2, and the clear yellow viscous solid of last gained is
14.5kg, yield 78.2%, the purity detecting free C through HPLC is: 96.5%.
The synthesis of his Wei crude product of reference examples 5 Dacca and purification
In a kettle., the ethanol that the free alkali C of 18kg is dissolved in 42kg, it is warming up to 50 DEG C.And make reactant liquor keep
At 50 DEG C, the ethanol solution of hydrogen chloride of the 20% of 1.8 equivalents is slowly added to above-mentioned reactant liquor.And it is little to react 4 at 50 DEG C
Shi Hou, is down to 15 DEG C by the temperature of reactant liquor, and reaction 3 hours at such a temperature.
Reacting liquid filtering, filter cake with 5kg alcohol flushing once, is dried and to obtain faint yellow solid 10.1kg, is his Wei of Dacca
Crude product, yield is 51.5%.The purity detecting his Wei crude product of Dacca through HPLC is: 90.2%.
The recrystallization of his Wei crude product of reference examples 6 Dacca
His Wei crude product of the Dacca of 10kg is dissolved in the methanol of 40kg, is heated to 50 DEG C, add the activated carbon of 500g, and
It is incubated 2h at 50 DEG C, filters, after concentrating the filtrate to 40kg, at 50 DEG C, add the acetone of 120kg, and stir at 50 DEG C
React 3 hours.Then slow cooling is to 20-25 degree, and stirring 3 hours at such a temperature.Filter, filter cake methanol and acetone body
The mixed solvent 2kg that long-pending ratio is 1:3 rinses once.Drying to obtain off-white color solid 7.2kg, yield 72%, HPLC detection purity is:
98.7%.
By the comparison of above-described embodiment Yu reference examples, the receipts of gained free alkali C in the cyclodehydration of the present invention reacts
Rate is 98.5%-98.6% (embodiment 2-5), and using the yield of the free alkali C obtained by prior art is 60.4%-
78.6% (reference examples 1-4), it can be seen that use method provided by the present invention, the yield of free alkali C can improve 20-30
Percentage point, meanwhile, the purity of gained free alkali C have also been obtained raising, and this greatly reduces the industry of his Wei of Dacca
The cost that metaplasia is produced.
Additionally, the present invention is during being obtained his Wei of Dacca by his Wei purifying crude of Dacca, the receipts of his Wei of gained Dacca
Rate is 87.1%-87.4%, and purity is 99.6%-99.7% (embodiment 8,9), and uses prior art to be purified gained
The yield of his Wei of Dacca is 72%, and purity is 98.7% (reference examples 6), it can be seen that, the method that the present invention provides, last gained
The yield of his Wei crude drug of Dacca improve 15 percentage points, purity is more than 99.6%, and the amount of contained single contaminant is less than
0.1%, illustrate that this synthetic method is the most cost-effective, but also can improve the drug safety of his Wei of Dacca.
In sum, the present invention for raw material, only passes through esterification with 4,4 '-two (2-haloacetyl) biphenyl (compound A)
Reaction and cyclodehydration react, and i.e. obtain the free alkali of his Wei of free alkali C, i.e. Dacca.Free alkali C carries out into salt, after purification again
I.e. obtain his Wei of highly purified Dacca.Synthesis technique is simple, be prone to purification, and synthesis cycle is short, products obtained therefrom yield high, application
By force.
Meanwhile, in this synthetic method, whole technique is without reference to the relatively harsh reaction of the conditions such as anhydrous, anaerobic, and does not has
Have and use the heavy metal toxic reagent such as palladium etc, environmentally friendly, and be conducive to controlling in his Wei crude drug of Dacca
Impurity and the amount of heavy metal, obtain his Wei crude drug of highly purified Dacca, with low cost, is suitable for that industry is big to be produced.
Although illustrate and describing the present invention with specific embodiment, but it will be appreciated that without departing substantially from the present invention's
May be made that in the case of spirit and scope many other change and amendment.It is, therefore, intended that in the following claims
Including all such changes and modifications belonged in the scope of the invention.
Claims (10)
1. the synthetic method of his Wei of Dacca, it is characterised in that comprise the following steps:
Step a: with 4,4 '-two (2-haloacetyl) biphenyl for raw material, with N-(methoxycarbonyl group)-Valine-L-PROLINE
In the presence of organic solvent and alkali, there is esterification, obtain intermediate B；
Step b: described intermediate B and ammonium acetate occur cyclodehydration to react and obtain in xylene solution at 100-120 DEG C
Free alkali C；
Step c: after described free alkali C with HCl reacts, obtains his Wei crude product of Dacca；
Step d: obtain his Wei of Dacca after his Wei crude product recrystallization of described Dacca；
Reaction scheme is as follows:
Wherein, X is Cl, Br or I.
The synthetic method of his Wei of Dacca the most according to claim 1, it is characterised in that in described step a, described alkali is selected from
Triethylamine, N, the one in the dimethylamine agueous solution of N-diisopropylethylamine, the ammonia of 25% or 20%.
The synthetic method of his Wei of Dacca the most according to claim 1 and 2, it is characterised in that in described step b, is being carried out
During the reaction of described cyclodehydration, constantly remove the water generated in reactant liquor, make water content control in reactant liquor exist
Less than 0.05%.
The synthetic method of his Wei of Dacca the most according to claim 1 and 2, it is characterised in that in described step b, described de-
In water cyclization, the pH of reactant liquor is 4-5.
The synthetic method of his Wei of Dacca the most according to claim 1, it is characterised in that the reaction dissolvent in described step c
Selected from ethanol, isopropanol, acetone, ethyl acetate, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane or 2-methyltetrahydrofuran
In at least one.
The synthetic method of his Wei of Dacca the most according to claim 1 or 5, it is characterised in that in described step c, described HCl
For the mixed solution of hydrogen chloride gas or hydrogen chloride gas and methanol or hydrogen chloride gas and ethanol mixed solution or
The mixed solution of the mixed solution of person's hydrogen chloride gas and ethyl acetate or hydrogen chloride gas and dioxane.
The synthetic method of his Wei of Dacca the most according to claim 1, it is characterised in that in described step d, recrystallization molten
At least one in methanol, ethanol, acetone, diisopropyl ether, methyl tertiary butyl ether(MTBE) and ethyl acetate of agent.
The synthetic method of his Wei of Dacca the most according to claim 1, it is characterised in that in described step d, molten at recrystallization
Adding he Wei Chunpin of Dacca in liquid is 1:100-1000 as crystal seed, described crystal seed with the mass ratio of his Wei crude product of described Dacca.
9. according to the synthetic method of his Wei of Dacca described in claim 1 or 7 or 8, it is characterised in that in described step d, heavily tie
Brilliant solution temperature is 15-45 DEG C.
The synthetic method of his Wei of Dacca the most according to claim 1, it is characterised in that 4 in described step a, 4 '-two
(2-haloacetyl) biphenyl is prepared by halogenating reaction by 4,4 '-diacetyl biphenyl.
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| CN107814789A (en) * | 2017-11-27 | 2018-03-20 | 常州寅盛药业有限公司 | A kind of synthetic method of his Wei initiation material of Dacca |
| CN108727345A (en) * | 2017-04-25 | 2018-11-02 | 广东东阳光药业有限公司 | A kind of preparation method of imidazole ring intermediate |
| CN109305962A (en) * | 2017-07-28 | 2019-02-05 | 扬子江药业集团有限公司 | A kind of refining methd of hydrochloric acid Da Latawei |
| CN110878090A (en) * | 2019-12-09 | 2020-03-13 | 南通常佑药业科技有限公司 | One-pot preparation process of NS5A protein inhibitor Daclatasvir |
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| CN110878090A (en) * | 2019-12-09 | 2020-03-13 | 南通常佑药业科技有限公司 | One-pot preparation process of NS5A protein inhibitor Daclatasvir |
| CN110878090B (en) * | 2019-12-09 | 2022-04-12 | 南通常佑药业科技有限公司 | One-pot preparation process of NS5A protein inhibitor Daclatasvir |
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