CN108218940A - Nucleoside phosphoramidate class compound, preparation method and the usage - Google Patents
Nucleoside phosphoramidate class compound, preparation method and the usage Download PDFInfo
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- CN108218940A CN108218940A CN201711317531.3A CN201711317531A CN108218940A CN 108218940 A CN108218940 A CN 108218940A CN 201711317531 A CN201711317531 A CN 201711317531A CN 108218940 A CN108218940 A CN 108218940A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/065—Preparation using different phases to separate parts of sample
Abstract
The invention belongs to medicinal chemistry arts; (S) 2 [[[(S) (1 is used for more particularly to nucleoside phosphoramidate class compound, preparation method and its as control comparisons product; 1 ' xenyl, 4 oxygroup)] [((2R; 3R; 4R; 5R) 5 (2; 4 dioxo 3,4 dihydro-pyrimidin 1 (2H) base) 4 fluorine, 3 hydroxyl, 4 methyltetrahydrofuran, 2 base) methoxyl group] phosphoryl] amino] related impurities are qualitative in isopropyl propionate bulk pharmaceutical chemicals quality research and/or the purposes of quantitative analysis.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to nucleoside phosphoramidate class compound, preparation method and its
(S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- are used for as control comparisons product
- 1 (2H)-yl of dioxo -3,4- dihydro-pyrimidins) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl]
Amino] related impurities are qualitative in isopropyl propionate bulk pharmaceutical chemicals quality research and/or the purposes of quantitative analysis.
Background technology
Hepatitis C Virus (HCV) infection be world-wide prevalence disease, global chronic infection more than 200,000,000,
Egyptian chronic infection rate is 15%, and Pakistan is 4.8%, and China is 3.2%, rank the world first three.Hepatitis C Virus
The diverse clinical manifestations of infection, gently to inflammation, weight to hepatic sclerosis, liver cancer.Chronic hepatitis C can also concurrent certain liver appearances
It is existing, including rheumatoid arthritis, drying property conjunctivokeratitis, lichen planus, glomerulonephritis, mixed type cryoglobulin blood
Disease, B cell lymphoma and porphyria cutanea tarda etc., it may be possible to caused by the reaction of body abnormal immune.And hepatitis hepatic sclerosis loses
During the compensatory phase, various complication can occur, such as ascites abdominal cavity infection, upper gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome,
The performances such as hepatic failure.
HCV belongs to flaviviridae hepatovirus virus, is pestivirus and Huang with other two category in flaviviridae
The gene structure of Tobamovirus is similar.At present, treating the standard method of HCV infection has interferon and interferon and Ribavirin connection
Close therapy.But, only 50% curer has this method reaction, and interferon has apparent side effect, such as popular
Cold like symptoms, weight lowers and fatigue and weak, and interferon and ribavirin combination therapy then generate sizable secondary work
With including haemolysis, anemia and tired etc..
In addition, developed include protease inhibitors, tetrahydrothiazole derivates, thiazole for treating the drug of HCV infection
Alkane and N- benzanilides, phenanthrenequione, helicase inhibitors, nucleoside polymerase inhibitor and gliotoxin, antisense phosphorothioate ester
Oligonucleotides, inhibitor, ribozyme and the nucleoside analog of translation dependent on IRES etc..At present, nucleoside phosphoric acid ester chemical combination
Object is used to treat the important R＆D direction that flaviviridae especially HCV infection is this field.
CN104031104A discloses a kind of novel nucleoside phosphoramidate compounds as shown in Equation 1, chemical name
For (2S) -2-, ((([1,1'- xenyls] -4- bases oxygroup) (((2,4- dioxo -3,4- dihydros are phonetic by (2R, 3R, 4R, 5R) -5-
Pyridine -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group) phosphoryl) amino) isopropyl propionate (with
Lower abbreviation " compound of formula I "),
CN104031104A reports (2S) -2- ((([1,1'- biphenyl] -4- bases oxygroup) (((2R, 3R, 4R, 5R) -5-
(- 1 (2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins) fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group) phosphorus
Acyl group) amino) isopropyl propionate is with excellent antiviral activity, to the small toxicity of cell, available for treatment flaviviridae disease
Poison, especially infection with hepatitis C virus.
(S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- dioxos -3,4-
Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] amino] propionic acid is different
Propyl ester is the stereoisomer of more than compound of formula I, has following structure shown in formula A：
The present inventor further study show that, formula A compounds or its hydrate, solvate or crystallization are to HCV
Virus has the inhibitory activity for being substantially better than compound of formula I, suitable for patent medicine.
It is well known that for human administration, for safety factor requirement, internal and international management organization is to bulk pharmaceutical chemicals
(API) it is not confirmed in or the limit of the uncertain impurity of toxicity provides very low, usually less than 0.1% (weight).It needs heavy to these
Impurity is wanted to be furtherd investigate, meets medicinal standard to ensure to be prepared, can be used in preparing safely and effectively pharmaceutical preparation
Bulk pharmaceutical chemicals.Impurity in bulk pharmaceutical chemicals may be to be generated due to the degradation of itself, it is also possible to from preparation method, example
Such as, the chemical derivative of impurity, synthesising by-product and degradation including being included in unreacted starting material, starting material
Product etc..By understand impurity chemical constitution and route of synthesis and by discriminating influence final product in impurity content ginseng
Number, can greatly enhance the control to related impurities.
(S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- dioxos -3,4-
Dihydro-pyrimidin -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] amino] propionic acid is different
Propyl ester may include the impurity in a variety of sources as bulk pharmaceutical chemicals, and hidden danger is brought to its druggability, safety and validity.Therefore,
The property of its by-product or impurity is studied, being detected control to these by-products or impurity is of great significance.
Invention content
First purpose of the present invention is to provide formula B, formula C, formula D, formula E and formula F compounds represented：
Preferably, formula B, formula C, formula D, formula E and the formula F compounds of preparation are detached respectively comprising the formula A compounds less than 1%
The purity of formula B, formula C, formula D, formula E and formula F compounds prepared by (being judged according to HPLC, area normalization method) or separation is extremely
It is 95% (being judged according to HPLC, area normalization method) less.In some embodiments, the formula B of preparation, formula C, formula D, formula are detached
The optical isomer purity of E and formula F compounds is at least 97%.In other embodiments, detach the formula B of preparation, formula C,
The optical isomer purity of formula D, formula E and formula F compounds is at least 98%.In other embodiments, the formula of preparation is detached
B, the optical isomer purity of formula C, formula D, formula E and formula F compounds is at least 99%.In other embodiments, separation system
Standby formula B, formula C, formula D, formula E and formula F compounds optical isomer purity be at least 99.5%.
Second object of the present invention is to provide the preparation method of formula B, formula C, formula D, formula E and formula F compounds：
The preparation method of the formula B compounds includes the following steps：In the presence of alkali, make 1- [(2R, 3R, 4R,
5R) the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans -2- bases of -3-] pyrimidine -2,4- (1H, 3H)-diketone and (S) -2-
[[(1,1 '-xenyl -4- oxygroup) (phenyl-pentafluoride oxygroup) phosphoryl] amino] isopropyl propionate reacts, and then detaches reaction solution system
.
In some embodiments, the preparation method of formula B compounds according to the present invention, by being selected from reverse-phase chromatography
The method separation reaction solution of method, supercritical fluid chromatography and Simulated Moving Bed Chromatography method is made.In some preferred embodiment party
In case, formula B compounds according to the present invention or its hydrate, solvate, crystallization or pharmaceutically acceptable salt preparation side
Method, wherein the reaction carries out under the protection of inert gas；Preferably, the inert gas is selected from nitrogen and argon gas.Its
Described in alkali be selected from term of the present invention illustrate described in alkali；Preferably, the alkali is selected from organolithium reagent, organic copper lithium
Reagent, sodium hydride and Grignard Reagent；It is further preferred that the alkali is grignard reagent；It is further preferred that the alkali
For tertiary butyl magnesium chloride and tertiary butyl magnesium bromide.In some specific embodiments, the mole of tertiary butyl magnesium chloride is 1-
[the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans -2- bases of (2R, 3R, 4R, 5R) -3-] pyrimidine -2,4- (1H, 3H)-two
About 1~4 times of ketone mole, preferably from about 2~3 times.
The preparation method of the formula C compounds includes the following steps：In the presence of alkali, make 1- [(2R, 3R, 4R,
5R) the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans -2- bases of -3-] pyrimidine -2,4- (1H, 3H)-diketone and (S) -2-
[[(S)-(1,1 '-xenyl -4- oxygroup) (phenyl-pentafluoride oxygroup) phosphoryl] amino] isopropyl propionate reacts, then separation reaction
Liquid is made.In some embodiments, the preparation method of formula C compounds according to the present invention, by be selected from RP chromatography,
The method of supercritical fluid chromatography and Simulated Moving Bed Chromatography method separation reaction solution is made.In some preferred embodiments
In, the preparation method of formula C compounds according to the present invention, wherein the reaction carries out under the protection of inert gas.At some
In specific embodiment, wherein the inert gas is selected from nitrogen and argon gas.In other embodiments, described in
Alkali be selected from term of the present invention illustrate described in alkali；Preferably, the alkali is selected from organolithium reagent, organic copper lithium reagent, hydrogen
Change sodium and Grignard Reagent；It is further preferred that the alkali is grignard reagent；It is further preferred that the alkali is tertiary fourth
Base magnesium chloride and tertiary butyl magnesium bromide.In some specific embodiments, 1- [the fluoro- 4- hydroxyls -5- of (2R, 3R, 4R, 5R) -3-
Methylol -3- methyl-tetrahydro furans -2- bases] mole of pyrimidine -2,4- (1H, 3H)-diketone is mole of tertiary butyl magnesium chloride
About 1.5~about 5 times of amount, preferably from about 2~about 3 times.
The preparation method of the formula D compounds includes the following steps：By (S) -2- [[[(S)-(1,1 '-xenyl -4-
Oxygroup)]-[((2R, 3R, 4R, 5R) -5- (- 1 (2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins) fluoro- 3- hydroxyls -4- first of -4-
Base tetrahydrofuran -2- bases) methoxyl group] phosphoryl] amino] isopropyl propionate is dissolved in organic solvent, adds under cryogenic
Benzoyl halogen, alkali, catalyst reaction are made.In some embodiments, the preparation method of formula D compounds according to the present invention,
The wherein described organic solvent is selected from methyl tertiary butyl ether(MTBE), methanol, isopropanol, ethyl alcohol, dichloromethane, acetone, isopropyl acetate
One or more of with tetrahydrofuran.It is further preferred that the organic solvent is selected from dichloromethane, acetone and tetrahydrofuran
One or more of.In other embodiments, the preparation method of formula D compounds according to the present invention, wherein described
Benzoyl halogen is selected from chlorobenzoyl chloride, benzoyl bromide and benzoyl iodide.It is further preferred that the benzoyl halogen is selected from benzoyl
Chlorine.In other embodiments, the preparation method of formula D compounds according to the present invention, wherein the alkali be selected from potassium carbonate,
Cesium carbonate, diisopropylamine, diisopropylethylamine, triethylamine, quinuclidine, naphthalene -1,8- diamines, 2,2,6,6- tetramethyl piperidines, 1,
11 carbon -7- alkene of 8- diazabicylos, 4-dimethylaminopyridine, pyridine, bis- C of 2,6-1-6Alkyl pyridine, tri- C of 2,4,6-1-6Alkane
Yl pyridines and its mixture.It is further preferred that the alkali is selected from triethylamine.In some embodiments, according to the present invention
Formula D compounds preparation method, wherein the catalyst be 4-dimethylaminopyridine (DMAP).
The preparation method of the formula E compounds includes the following steps：In the presence of alkali, make 1- [(2S, 3R, 4R,
5R) the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans -2- bases of -3-] pyrimidine -2,4- (1H, 3H)-diketone and (S) -2-
The reaction of [[(S)-(1,1'- xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphoryl] amino] isopropyl propionate is made.It is excellent at some
In the embodiment of choosing, the preparation method of formula E compounds according to the present invention, wherein the reaction is under the protection of inert gas
It carries out.In some embodiments, wherein the inert gas is selected from nitrogen and argon gas.In other embodiments,
The alkali be selected from term of the present invention illustrate described in alkali；Preferably, the alkali is selected from organolithium reagent, organic copper lithium tries
Agent, sodium hydride and Grignard Reagent；It is further preferred that the alkali is grignard reagent；It is further preferred that the alkali is
Tertiary butyl magnesium chloride and tertiary butyl magnesium bromide.
The preparation method of the formula F compounds includes the following steps：In the presence of alkali, make 1- [(2R, 3R, 4R,
5R) -3- chloro-4-hydroxyls -5- methylols -3- methyl-tetrahydro furans -2- bases] pyrimidine -2,4- (1H, 3H)-diketone and (S) -2-
The reaction of [[(S)-(1,1'- xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphoryl] amino] isopropyl propionate is made.It is excellent at some
In the embodiment of choosing, the preparation method of formula F compounds according to the present invention, wherein the reaction is under the protection of inert gas
It carries out.In some embodiments, the inert gas is selected from nitrogen and argon gas.In other embodiments, described in
Alkali be selected from term of the present invention illustrate described in alkali；Preferably, the alkali be selected from organolithium reagent, organic copper lithium reagent,
Sodium hydride and Grignard Reagent；It is further preferred that the alkali is grignard reagent；It is further preferred that the alkali is uncle
Butylmagnesium chloride and tertiary butyl magnesium bromide.
Third object of the present invention be to provide a kind of positioning, in quantitative A compounds as the formula B of by-product, formula C,
The HPLC methods of formula D, formula E and formula F compounds.May exist when formula A compounds are as production of raw medicine, in product certain
Amount as the formula B of by-product, formula C, formula D, formula E and formula F compounds.To meet the requirement of drug, need to detect and control work
Content for the formula B of impurity, formula C, formula D, formula E and formula F compounds.Therefore, formula B, formula C, formula D, formula E and formula F compounds can be with
As control comparisons product, ownership and positioning applied to related impurities in HPLC method analysis mode A compounds can be used for formula Aization
Close the quantitative analysis as the formula B of by-product, formula C, formula D, formula E and formula F compounds and the quality for formula A compounds in object
Analysis.The present invention the HPLC methods using formula B, formula C, formula D, formula E and formula F compound analysis formula A compounds include with
Lower step：
1) prepare respectively containing formula B, formula C, formula D, formula E, formula F, formula A compounds positioning solution；
2) the system suitability solution containing formula B, formula C, formula D, formula E, formula F and formula A compounds is prepared；With
3) pass through high-efficient liquid phase color using system suitability solution made from step 1) positioning solution obtained and step 2)
Spectrometry separate type B, formula C, formula D, formula E, formula F and formula A compounds, and determine formula B, formula C, formula D, formula E, formula F and formula A compounds
Position and content.
It is according to the present invention to utilize formula B, formula C, formula D, formula E, formula F and formula A compounds in some specific embodiments
HPLC methods, the preparation method of the wherein system suitability solution of step 2) includes：
I) accurately weighed formula B, formula C, formula D, formula E and formula F compounds, are dissolved respectively with alcoholic solution, obtain five parts of solution；With
II) accurately weighed formula A compounds, are dissolved with alcoholic solution, add step I) made from five parts of solution, use again later
Alcoholic solution dilutes, and obtains system suitability solution, it is preferable that it is molten that the alcoholic solution is selected from methanol, ethyl alcohol, propyl alcohol and isopropanol
Liquid, it is highly preferred that the alcoholic solution is methanol solution.
Herein, formula B, formula C, formula D, formula E, formula F and formula A compounds further include the hydrate of the compound, solvent
Close object, crystallization or pharmaceutically acceptable salt.
Term explanation
Unless otherwise defined, all technical and scientific terms used herein has and common skill of the art
The normally understood identical meaning of art personnel.
" optical isomer " of the invention refers to that molecular structure is identical, and physicochemical properties are close, but optical activity is different
Substance.For given chemical constitution, different optically active compounds is referred to as optical isomer, in addition to being relatively mirror
As except, they are identical.In the description of optically active compound, prefix D and L or R and S are for expression and the hand of molecule
The related absolute configuration in property center.Prefix (+) and (-) or d and l are used for the rotation side of linearly polarized light caused by appointed compound
To.Represent that compound is left-handed with (-) or l.Prefix is dextrorotation for the compound of (+) or d.Many organic compounds are with light
It learns active form to exist, i.e., they can make the Plane Rotation of linearly polarized light.
In the present invention, when specific isomers in the composition of mixture more than 50% when, racemic mixture " is rich in "
The specific isomers.Substantially free refers to work as to be determined using the conventional use of traditional analysis of those skilled in the art
When, which includes that less than about 10% unwanted isomers, such as the amount of unwanted isomers 10% can be less than,
For example, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or even less.Containing different about needed for 95% or more
The compound rich in isomers of structure body is referred to herein as " substantially pure " isomers.Containing about needed for 99% or more
The compound rich in isomers of isomers is referred to herein as " pure " optical isomer.Any " purity of optical isomer " can
Confirmed with using traditional analysis method, as proper method can easily be established by this field and well known (such as
Chiral high pressure liquid chromatography (HPLC), chiral gas chromatography (GC), the nuclear magnetic resonance (NMR) using chiral shift reagent
Deng) be kept completely separate optical isomer with its enantiomter or diastereoisomer, it is calculated by area normalization method.
" grignard reagent " of the invention refers to that general formula is R1The reagent of MgX, wherein R1Selected from fat-based and aromatic radical, X is halogen
Element.The grignard reagent is produced by halogenated hydrocarbons and magnesium metal in anhydrous ether or tetrahydrofuran.
" organolithium reagent " of the invention refers to that general formula is R2The reagent of-Li, wherein R2Selected from fat-based and aromatic radical.It is described
Organolithium reagent produced in anhydrous ether or tetrahydrofuran by halogenated hydrocarbons and lithium metal.
" organic copper lithium reagent " of the invention refers to that general formula is (R3)2The reagent of CuLi, wherein R3Selected from fat-based and fragrance
Base.
" halogenated hydrocarbons " of the invention refers to halogenated aliphatics or halogenated aromatic compound.
" fat-based " of the invention refers to the saturated or unsaturated aliphatic group of linear chain or branch chain, preferably containing 1 to 6 carbon
The linear chain or branch chain group of atom, the linear chain or branch chain group of further preferably 1 to 3 carbon atom, non-limiting examples
Including methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl propylenes
Base, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, ethylene
Base, acetenyl etc..Alkyl can be substituted or unsubstituted, and when substituted, substituent group workable can connect any
On contact.
" aromatic radical " of the invention refers to containing the heteroatomic aromatic group of zero or more.The hetero atom for O, S,
N.Suitable aromatic group includes but not limited to phenyl, naphthalene, pyridyl group, pyrazolyl, oxazolyls, thiazolyl, thienyl, furan
Mutter base, pyrrole radicals, isoxazolyls, isothiazolyl, imidazole radicals, triazolyl, tetrazole radical, oxadiazolyls, thiadiazolyl group, pyrimidine radicals,
Pyridazinyl, pyrazinyl and triazine radical.
" alkali " of the invention means the compound that can make hydroxyl or amino deprotonation.The example of alkali includes but not limited to,
(the C combined with alcoholic solvent1-6Alkyl) oxide ((C1-6Alkyl) OM), wherein (C1-6Alkyl) oxide includes but not limited to
MeO-, EtO-, n-PrO-, i-PrO-, t-BuO-, i-AmO- (isoamoxy) etc., and wherein M is alkali metal cation, such as
Li+、Na+、K+Deng.Alcoholic solvent includes (C1-6Alkyl) OH, for example, such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, the tert-butyl alcohol, different
Amylalcohol etc..Non- alkoxy base, such as sodium hydride, lithium hexamethyldisilazane amine sodium, lithium hexamethyldisilazane amine can also be used
Lithium, lithium diisopropylamide, calcium hydride, sodium carbonate, potassium carbonate, cesium carbonate, DBU (1,8- diazabicylos [5.4.0] 11
Carbon -7- alkene), DBN (1,5- diazabicyclos [4.3.0] nonyl- 5- alkene), Grignard Reagent such as (C1-6Alkyl) Mg (halogen), packet
It includes but is not limited to methyl-magnesium-chloride, methyl-magnesium-bromide, tertiary butyl magnesium chloride, tertiary butyl magnesium bromide etc..
" halogen " of the invention refers to fluorine, chlorine, bromine or iodine.
Description of the drawings
Fig. 1 is the dissymmetrical structure cell schematics that formula A compounds normal heptane solvent closes object monocrystalline.
Fig. 2 is the unit cell schematic diagram that formula A compounds normal heptane solvent closes object monocrystalline.
Fig. 3 is the typical HPLC chromatogram of by-product formula B compound solutions.
Fig. 4 is the typical HPLC chromatogram of by-product formula C compound solutions.
Fig. 5 is the typical HPLC chromatogram of by-product formula D compound solutions.
Fig. 6 is the typical HPLC chromatogram of by-product formula E compound solutions.
Fig. 7 is the HPLC figures of formula A compounds and by-product formula B, formula C, formula D, formula E compounds and other impurity mixing sample introductions
Spectrum, wherein 25.573min are formula A compounds, and 23.649min is by-product formula B compounds, and 48.625min is by-product formula Cization
Object is closed, 39.600min is by-product formula D compounds, and 24.808min is by-product formula E compounds.
Specific embodiment
The present invention is further elaborated, but the present invention is not limited to these Examples with reference to embodiment.Below
The material used in embodiment is commercially available unless otherwise specified.
Embodiment 1 (S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- dioxies
- 1 (2H)-yl of generation -3,4- dihydro-pyrimidins) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] amino]
Isopropyl propionate
Step 1 (S) -2- [[(1,1'- xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphoryl] amino] isopropyl propionate
Synthesis
In 50L glass reaction kettles, under nitrogen protection, phosphorus oxychloride (1.53kg, 10mol) and dichloromethane are added in
(10L), stirring, is cooled to less than -30 DEG C.Dichloromethane (5L) solution of triethylamine (1.01kg, 10mol) is added dropwise, was added dropwise
Journey, temperature is less than -30 DEG C in holding.It is added dropwise, the tetrahydrofuran (3.4L) of 4- xenols (1.7kg, 10mol) is slowly added dropwise
Solution drips and finishes stirring 30min.Temperature adds in l-Alanine isopropyl ester hydrochloride (1.68kg, 10mol) less than -30 DEG C in control,
Dichloromethane (8.0L) solution of triethylamine (2.02kg, 20mol) is added dropwise, stirs 30min.0 DEG C or so is warming up to, five fluorine are added dropwise
Phenol (1.84kg, 10mol), dichloromethane (7.0L) solution of triethylamine (1.01kg, 10mol), during dropwise addition, reaction is put
Heat heating, is added dropwise, and Inner temperature is warmed to room temperature, and after the reaction was complete, filtering, filter cake is washed with dichloromethane (2.5L × 4), is merged
Filtrate washs filtrate with purified water (25L), liquid separation, and organic phase is concentrated under reduced pressure, and adds in heptane (5L × 2) band solvent, centrifuges,
Vacuum drying, weighs, obtains off-white powder shape title compound.
Step 2 (S) -2- [[(S)-(1,1'- xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphoryl] amino] propionic acid isopropyl
The synthesis of ester
In 30L reaction kettles, under nitrogen protection, (S) -2- [[(1,1 '-xenyl -4- oxygroup) (phenyl-pentafluoride oxygroup) is added in
Phosphoryl] amino] isopropyl propionate (3.70kg, 7.0mol), methyl tertiary butyl ether(MTBE) (2.40kg), normal heptane (9.0kg), three second
Amine (77g, 0.7mol), Pentafluorophenol (43g, 0.21mol) are heated to 40 DEG C, strength mechanical agitation.After the reaction was complete, centrifugation,
Vacuum drying, obtains title compound.
Step 3 (S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- dioxies
- 1 (2H)-yl of generation -3,4- dihydro-pyrimidins) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] amino]
The synthesis of isopropyl propionate
In 50L glass reaction kettles, 1- [the fluoro- 4- hydroxyls -5- methylols -3- methyl four of (2R, 3R, 4R, 5R) -3- is added in
Hydrogen furans -2- bases] pyrimidine -2,4- (1H, 3H)-diketone finished product (1.30kg, 5.0mol), tetrahydrofuran (15.6L), stirring, nitrogen
Gas shielded is cooled to less than -10 DEG C.Tertiary butyl magnesium chloride solution (8.0L, 8.0mol) is added dropwise, drop finishes, and 0~5 DEG C the reaction was continued
1h.Add in (S) -2- [[(S)-(1,1 '-xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphoryl] amino] isopropyl propionate finished product
(2.12kg, 4.0mol), is added dropwise, 5~10 DEG C of reactions, is sampled after 10~11h, and HPLC monitoring after the reaction was complete, is cooled to
0 DEG C is quenched reaction hereinafter, adding in 2N hydrochloric acid (4.0L, 8.0mol) into reaction solution.Process control temp is quenched at 0~10 DEG C.
It is added dropwise, stirs 10min.It is concentrated under reduced pressure, is evaporated to obtain solid-liquid residue, add in ethyl acetate (40.0L) and purified water
(20.0L), liquid separation.5% aqueous sodium carbonate (10.0L) washing is added in into organic phase, is then washed, filters, is spin-dried for, again
Dichloromethane 7.0L is added in, concentration obtains oily foamed, and isopropyl acetate (15.0L), dissolved clarification are added in into oily foamed
Afterwards, cool down, a large amount of white precipitates are precipitated.Cooling, filtering, dry cake obtain off-white powder shape title compound.
Step 4 (S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- dioxies
- 1 (2H)-yl of generation -3,4- dihydro-pyrimidins) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] amino]
Isopropyl propionate refines
In 30L reaction kettles, addition (S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroup)]-[((2R, 3R, 4R, 5R) -
5- (- 1 (2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins) fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group]
Phosphoryl] amino] isopropyl propionate crude product (4.80kg), isopropyl acetate (24.0L), stirring, heating dissolved clarification.Add in activated carbon
(144g) stirs 30min, filters while hot, cool down, filtering, dry cake, obtains title compound, and purity is more than 98%.1HNMR
(300MHz,DMSO)δ:11.48(s,1H),7.67(d,2H),7.64-7.62(m,2H),7.59(d,1H),7.47(t,2H),
7.37(t,1H),7.33(d,2H),6.04(d,1H),6.02(d,1H),5.83(d,1H),5.57(d,1H),4.89-4.84
(m,1H),4.42-4.39(m,1H),4.29-4.24(m,1H),4.05-4.02(m,1H),3.88-3.82(m,2H),1.29-
1.24(m,6H),1.16-1.15(m,6H)。ESI-MS m/z:604.2[M+H]-。31P NMR(300MHz,DMSO-d6):δ
4.07ppm。
Embodiment 2：(S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- bis-
- 1 (2H)-yl of oxo -3,4- dihydro-pyrimidins) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] ammonia
Base] isopropyl propionate configuration confirmation
The compound (15mg) of the preparation of embodiment 1 is weighed in 3mL bottles, adds in dichloromethane/normal heptane (5mL, volume
Than being 2:1) in mixed solvent system, the clear solution that shakes covers bottle with sealed membrane and hole, room temperature is pricked above
It is lower to place 6 days, obtain monocrystalline.Absolute configuration determines by measuring its Advances in crystal X-ray diffraction collection of illustrative plates, detecting instrument Agilent
Super single crystal diffractometers, test condition is copper target, pipe presses 40kv, pipe stream 40mA, and crystallographic structural analysis method is direct method
(SHELXTL and OLEX2), the single crystal structural data table measured are shown in Table 1, and single crystal diffraction collection of illustrative plates is shown in Fig. 1,2.
1 mono-crystalline structures information table of table
The present inventor measures formula A compounds using the method for experimental example in CN104031104A 1 and HCV 1b is answered
The EC of system50, experimental result shows that formula A compounds of the invention are to the EC of HCV 1b replicons50Be worth is 0.036 μM, hence it is evident that
Better than the EC of 1 compound of formula500.120 μM of value.In addition, the method with reference to Chinese patent application CN105985355A embodiments 2 is examined
The activity of the formula A compound HCV-Ab IgG -1a replicons of the present invention is surveyed, shows the formula A compounds of the present invention to HCV 1a replicons
EC50It is 0.01 μM to be worth, and is also substantially better than the EC of 1 compound of formula500.05 μM of value.
Embodiment 3 (S) -2- [[[(R)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- dioxies
- 1 (2H)-yl of generation -3,4- dihydro-pyrimidins) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] amino]
Isopropyl propionate
The preparation method that the preparation method is the same as that of Example 1, the difference is that use raw material (S) -2- [[(1,1 '-xenyl -4- oxygen
Base) (phenyl-pentafluoride oxygroup) phosphoryl] amino] isopropyl propionate replacement (S) -2- [[(S)-(1,1 '-xenyl -4- oxygroups) (five
Fluorophenoxy) phosphoryl] amino] isopropyl propionate and post processing mode be that reaction solution is made mark by preparing liquid phase separation
Compound is inscribed, purity is 99.69% (HPLC).ESI-MS m/z:606.2[M+H]+。1HNMR(300MHz,DMSO-d6)δ:
11.46(1H,s),7.67-7.65(2H,m),7.63-7.62(2H,m),7.58-7.56(1H,d),7.46-7.43(2H,m),
7.36-7.33(1H,m),7.29-7.28(2H,m),6.03(1H,d),6.07(1H,d),5.88-5.86(1H,bs),5.66-
5.65(1H,d),4.89-4.85(1H,m),4.48-4.46(1H,m),4.34-4.32(1H,m),4.11-4.10(1H,m),
3.87-3.85(1H,m),3.82-3.79(1H,m),1.28-1.24(6H,m),1.17-1.15(6H,t).31P NMR
(300MHz,DMSO-d6):δ3.86ppm.
Embodiment 4 (2S) -2- [[[[(S)-(1,1'- xenyls) -4- oxygroups]-[((2R, 3R, 4R, 5R) -2- [[S- (1,
1'- xenyls) -4- oxygroups]-[(S)-(1- isopropoxy -1- oxopropyl -2- bases) amino] phosphinylidyne oxygroup] -5- [2,4- bis-
- 1 (2H)-yl of oxo -3,4- dihydro-pyrimidins] the fluoro- 3- methyltetrahydrofurans -2- bases of -3-]-methoxyl group] phosphoryl] amino] propionic acid
Isopropyl ester
Title compound, purity are obtained with the reaction mother liquor for preparing 1 step 3 of liquid phase separation embodiment：97.06%
(HPLC)。ESI-MS m/z:951.4[M+H]+。1HNMR(300MHz,DMSO-d6)δ:11.4,7.67-7.65(1H,m),
7.66-7.65(2H,m),7.63-7.59(6H,m),7.46-7.42(4H,m),7.36-7.33(4H,m),7.31-7.29(2H,
m),6.35-6.30(1H,m),5.98-5.93(1H,bs),5.61-5.59(1H,m),4.91-4.82(3H,m),4.62-4.59
(1H,m),4.39-4.36(1H,m),4.27-4.24(1H,m),3.92-3.82(1H,m),1.40-1.35(3H,m),1.30-
1.26(6H,m),1.16-1.13(12H,m).31P NMR(300MHz,DMSO-d6):δ 3.96,3.83ppm.
Embodiment 5 (2R, 3R, 4R, 5R) -2- [[[(S)-(1,1'- xenyls) -4- oxygroups]-[(S)-(1- isopropoxies -
1- oxo-propyll -2- bases) amino] phosphorus acyloxymethyl] -5- [- 1 (2H)-yl of 2,4- dioxo -3,4- dihydropyridines] -4- is fluoro-
4- methyltetrahydrofuran -3- bases] benzoic ether
Formula A compounds (3g) made from embodiment 1 are dissolved in dichloromethane (20mL), are added in 100mL reaction bulbs, are cooled down
To 0 DEG C, chlorobenzoyl chloride (1.05g) is slowly added dropwise, finishes, kept for 0 DEG C, triethylamine (1.01g), catalytic amount 4- diformazans is slowly added dropwise
Aminopyridine (DMAP), finishes and is warmed to room temperature, and reacts 2 hours, is spin-dried for, and crosses column, obtains title compound.Purity：98.69%
(HPLC)。ESI-MS m/z:710.3[M+H]+。1HNMR(300MHz,DMSO-d6)δ:11.54(1H,s),8.04-8.02(2H,
m),7.76-7.75(1H,m),7.73-7.70(1H,d),7.61-7.59(4H,m),7.58-7.55(2H,m),7.46-7.43
(2H,m),7.36-7.33(1H,d),7.26-7.24(2H,m),6.14-6.10(1H,d),6.05-6.00(1H,m),5.66-
5.64(1H,d),5.57-5.56(1H,m),4.85-4.80(1H,m),4.50(1H,m),4.45-4.41(1H,m),4.36-
4.31(1H,m),3.85-3.78(1H,m),1.41-1.37(3H,d),1.23-1.21(3H,d),1.14-1.12(6H,m).31P
NMR(300MHz,DMSO-d6):δ3.99ppm.
Embodiment 6 (S) -2- [[[(S) -1,1 '-xenyl -4- oxygroups]-[((2R, 3R, 4R, 5S) -5- (2,4- dioxies
- 1 (2H)-yl of generation -3,4- dihydro-pyrimidins) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] amino]
Isopropyl propionate
Take the fluoro- 4- methyl -5- oxos -2- benzoyloxymethy tetrahydrofurans of (2R, 3R, 4R) -3- benzoyloxys -4-
(30g) adds in dichloromethane, is cooled to -10 DEG C hereinafter, bis- (the 2- methoxy second of dihydro of trifluoroethanol improvement that dropwise addition prepares
Oxygroup) sodium aluminate go back original reagent, it is added dropwise, is warming up to room temperature, after the reaction was complete, gains are dissolved in dichloromethane by post processing
Alkane adds in thionyl chloride, is heated to flowing back at 50 DEG C.TLC is monitored, and after reaction, concentrate is dissolved in second by reaction solution concentration
In nitrile, -5 DEG C are cooled to, Trimethylsilyl trifluoromethanesulfonate (TMSTof) is added in, after 30 minutes, front three is added dropwise into reaction solution
The uracil of base silicon protection is warming up to 80 DEG C, reaction.It treats after reaction, gains are dissolved in absolute methanol by post processing,
- 5 DEG C are cooled to, sodium methoxide solution is added dropwise, drop finishes, is warmed to room temperature, and LC-MS monitoring treats that the reaction was complete, post-processes, obtain 1-
[the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans -2- bases of (2S, 3R, 4R, 5R) -3-] pyrimidine -2,4- (1H, 3H)-two
Ketone.With 1- [the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans -2- bases of (2S, 3R, 4R, 5R) -3-] pyrimidine -2,4- (1H,
3H)-diketone and (S) -2- [[(S)-(1,1'- xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphoryl] amino] isopropyl propionate
For raw material, target compound is prepared with reference to the method for 1 step 3 of embodiment.Purity：98.86% (HPLC).ESI-MS m/
z:606.2[M+H]+.1HNMR(300MHz,DMSO-d6)δ:11.42(1H,s),7.66-7.64(2H,m),7.64-7.62(2H,
m),7.50-7.47(1H,d),7.46-7.44(2H,m),7.37-7.35(1H,m),7.31-7.30(2H,m),6.12-6.08
(1H,d),6.03-5.98(1H,d),5.87(1H,bs),5.65-5.63(1H,d),4.90-4.85(1H,m),4.31-4.26
(1H,m),4.13-4.08(1H,m),4.05-3.98(1H,m),3.85-3.80(1H,m),1.37-1.33(3H,d),1.27-
1.26(3H,d),1.15-1.17(6H,dd).31P NMR(300MHz,DMSO-d6):δ3.80ppm.
Embodiment 7 (S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- dioxies
Generation -3,4- dihydro-pyrimidins-(2H) -1- bases) -4- chloro-3-hydroxyl -4- methyltetrahydrofuran -2- bases) methoxyl group] phosphoryl] ammonia
Base] isopropyl propionate
Step 3 that the preparation method is the same as that of Example 1, the difference is that by 1- [the fluoro- 4- hydroxyls -5- hydroxyl first of (2R, 3R, 4R, 5R) -3-
Base -3- methyl-tetrahydro furans -2- bases] pyrimidine -2,4- (1H, 3H)-diketone replaces with 1- [the chloro- 4- hydroxyls of (2R, 3R, 4R, 5R) -3-
Base -5- methylol -3- methyl-tetrahydro furans -2- bases] pyrimidine -2,4- (1H, 3H)-diketone, title compound, purity is made：
97.18% (HPLC).ESI-MS m/z:622.1[M+H]+.1HNMR(300MHz,DMSO-d6)δ:11.51(1H,s),7.70-
7.65(5H,m),7.50-7.46(2H,m),7.39-7.38(1H,m),7.36-7.34(2H,m),6.31(1H,s),6.08-
6.13(1H,d),6.16-6.15(1H,m),5.58-5.57(1H,d),4.92-4.87(1H,m),4.47-4.44(1H,m),
4.36-4.32(1H,m),4.13-4.11(1H,m),3.97(1H,m),3.91-3.86(1H,m),1.47(3H,s),1.31-
1.29(3H,d),1.17-1.15(6H,t).31P NMR(300MHz,DMSO-d6):δ4.09ppm.
Positioning, the quantitative analysis of 8 formula B of embodiment, formula C, formula D and formula E compounds
By-product positions the preparation of solution：Precision weighs by-product formula B, formula C, formula D and each 10mg of formula E compounds, is placed in
It in 10mL volumetric flasks, is dissolved with methanol and is diluted to scale, shaken up, as positioning solution.(formula B, formula C, formula D and formula E chemical combination
Object concentration is respectively 1.0mg/mL).
The preparation of formula A compound control product solution：Precision weighs formula A compound control product 20mg, is placed in 10mL volumetric flasks
In, methanol is added to dissolve and is diluted to scale, shake up to get.(formula A compound concentrations are 2mg/mL).
The preparation of system suitability solution：Accurate modus ponens A compound control 20mg, are placed in 10mL volumetric flasks, first plus few
Methanol dissolving is measured, adds each by-product positioning solution of 0.2mL, methanol dilution to scale shakes up, as system suitability solution
(formula A compound concentrations are 2mg/mL, and formula B, formula C, formula D and formula E compound concentrations are respectively 20 μ g/mL).
Above-mentioned positioning solution and system suitability solution are taken, measures 5 μ L injection chromatographic columns (Agilent ZORBAX
Eclipse Plus C18,4.6 × 150mm, 3.5 μm), using water as mobile phase A, using methanol as Mobile phase B, flow velocity 1.0mL/
Min, according to 1 gradient elution sample of table：
Table 1
Using UV detector position and content are determined at 254nm wavelength.
The guarantor of impurity formula B, formula C, formula D and formula E the retention time of the compound and each compound in Fig. 7 in comparison diagram 3-6
The time is stayed, retention time unanimously can determine impurity formula B, formula C, formula D, the position of formula E compounds in the figure 7.Experimental result is shown
Show, by-product formula A compounds are at 25.573min, by-product formula B compounds are by-product formula C at 23.649min in the figure 7
Compound is at 48.625min, by-product formula D compounds are at 39.600min, by-product formula E compounds are 24.808min
Place, is specifically shown in Fig. 3~Fig. 7.Although being described in detail above to the present invention, however it is understood by skilled practitioners that
The present invention can be carry out various modifications and be changed under the premise of without departing from the spirit and scope of the present invention.The right model of the present invention
The detailed description for being not limited to be made above is enclosed, and claims should be belonged to.
Claims (10)
1. formula B, formula C, formula D, formula E and formula F compounds represented：
2. the method for formula B compounds represented,
Including in the presence of alkali, make 1- [the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans of (2R, 3R, 4R, 5R) -3- -
2- yls] pyrimidine -2,4- (1H, 3H)-diketone and (S) -2- [[(1,1 '-xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphoryl] ammonia
Base] isopropyl propionate reaction, it then detaches reaction solution and is made.
3. the method for formula C compounds represented,
Including in the presence of alkali, make 1- [the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans of (2R, 3R, 4R, 5R) -3- -
2- yls] pyrimidine -2,4- (1H, 3H)-diketone and (S) -2- [[(S)-(1,1 '-xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphinylidynes
Base] amino] isopropyl propionate reaction, it then detaches reaction solution and is made.
4. the method for formula D compounds represented,
Including by (S) -2- [[[(S)-(1,1 '-xenyl -4- oxygroups)]-[((2R, 3R, 4R, 5R) -5- (2,4- dioxo -3,
4- dihydro-pyrimidins -1 (2H)-yl) the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group] phosphoryl] amino] propionic acid
Isopropyl ester is dissolved in organic solvent, is added in benzoyl halogen, alkali, catalyst reaction and is made.
5. the method for formula E compounds represented,
Including in the presence of alkali, make 1- [the fluoro- 4- hydroxyls -5- methylols -3- methyl-tetrahydros furans of (2S, 3R, 4R, 5R) -3- -
2- yls] pyrimidine -2,4- (1H, 3H)-diketone and (S) -2- [[(S)-(1,1'- xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphinylidynes
Base] amino] isopropyl propionate reaction be made.
6. the method for formula F compounds represented,
Including in the presence of alkali, make 1- [(2R, 3R, 4R, 5R) -3- chloro-4-hydroxyl -5- methylol -3- methyl-tetrahydros furans -
2- yls] pyrimidine -2,4- (1H, 3H)-diketone and (S) -2- [[(S)-(1,1'- xenyl -4- oxygroups) (phenyl-pentafluoride oxygroup) phosphinylidynes
Base] amino] isopropyl propionate reaction be made.
7. according to any one of them method of claim 2,3,5 and 6, wherein the reaction under the protection of inert gas into
Row, it is preferable that the inert gas is selected from nitrogen and argon gas.
8. according to any one of them method of claim 2,3,5 and 6, wherein the alkali is selected from organolithium reagent, organic
Copper lithium reagent, sodium hydride and Grignard Reagent.
9. according to the method described in claim 4, the wherein described alkali is selected from potassium carbonate, cesium carbonate, diisopropylamine, diisopropyl
Ethamine, triethylamine, quinuclidine, naphthalene -1,8- diamines, 2,2,6,6- tetramethyl piperidines, 11 carbon -7- alkene of 1,8- diazabicylos,
4-dimethylaminopyridine, pyridine, bis- C of 2,6-1-6Alkyl pyridine, tri- C of 2,4,6-1-6Alkyl pyridine and its mixture, it is described
Catalyst is 4-dimethylaminopyridine.
10. formula B according to claim 1, the purposes of formula C, formula D, formula E and formula F compounds represented as control comparisons product.
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