CN105924431A - Synthesis process for compound crizotinib - Google Patents
Synthesis process for compound crizotinib Download PDFInfo
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- CN105924431A CN105924431A CN201610375575.0A CN201610375575A CN105924431A CN 105924431 A CN105924431 A CN 105924431A CN 201610375575 A CN201610375575 A CN 201610375575A CN 105924431 A CN105924431 A CN 105924431A
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- 0 C[C@](c(c(Cl)ccc1F)c1Cl)OC(C=CC=C(*)C1)=C1[N+]([O-])=O Chemical compound C[C@](c(c(Cl)ccc1F)c1Cl)OC(C=CC=C(*)C1)=C1[N+]([O-])=O 0.000 description 5
- CKONUUZQLZYCQQ-ZCFIWIBFSA-N C[C@H](c(c(C)ccc1F)c1Cl)O Chemical compound C[C@H](c(c(C)ccc1F)c1Cl)O CKONUUZQLZYCQQ-ZCFIWIBFSA-N 0.000 description 1
- JAOYKRSASYNDGH-SCSAIBSYSA-N C[C@H](c(c(Cl)ccc1F)c1Cl)O Chemical compound C[C@H](c(c(Cl)ccc1F)c1Cl)O JAOYKRSASYNDGH-SCSAIBSYSA-N 0.000 description 1
- OPCWPQMTGTWVDG-RXMQYKEDSA-N C[C@H](c(c(Cl)ccc1F)c1Cl)OS(C)(=O)=O Chemical compound C[C@H](c(c(Cl)ccc1F)c1Cl)OS(C)(=O)=O OPCWPQMTGTWVDG-RXMQYKEDSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention provides a new synthesis method for crizotinib. An atomic economic reaction is adopted to reduce environmental pollution. A high-optical purity raw material is obtained by chiral prolinol induced chiral reduction; a chiral centre is constructed through an SN2 substitution reaction; post-processing and purification difficulties caused by Mitsunobu reaction are overcome. Malononitrile derivative is constructed by adopting a coupling reaction of malononitrile and bromo-pyridinium derivative; N,N-dicarboamide derivatives are obtained by performing aminolysis on N,N-dimethylamine hydrochloride; in the N,N-dicarboamide derivatives, N,N-dimethylamine serving as an easy-to-leave group and hydrazine perform a ring closing reaction to construct a pyrazolone ring, so that an expected final product, namely crizotinib, is obtained. According to the method, though continuous steps are used, the reaction of each step is high, the optical purity is high, and the total yield is also high. In addition, raw materials used in the synthesis method are low in cost and easily obtained; the using amount of a catalyst is small; total cost is easy to control. An operating process is simple and convenient and easy to control, and is suitable for industrial production.
Description
Technical field
The present invention relates to technical field of chemical medicine, be specifically related to a kind of small-molecule drug gram azoles synthesis technique for Buddhist nun,
For treating advanced Non-small cell lung.
Background technology
The treatment of advanced Non-small cell lung (non-small cell lung cancer, NSCLC) has been enter into individuation
The New Times of targeted therapy, the treatment under targeting molecule mark instructs has become as the focus studied at present.The epidermis that continues is raw
After growth factor receptor body (EGFR) sudden change, echinoderm microtubule-associated protein 4 (EML4) and change lymphom kinase (ALK) are merged
Gene, c-Met, Ros sarcoma cancerigenic factor (ROSl) etc. become the new target to advanced NSCLC treatment with directive significance
Point.Wherein, EML4-ALK fusion gene is to be inserted by No. 2 the short arm of a chromosome to cause, and makes the kinases of two EML4-ALK molecules
District be combined with each other, and activates downstream passages by autophosphorylation, thus causes cell to vicious transformation.C-Met is a kind of former cancer
Gene, protein product of its coding cell proliferation, break up and migrate in play a significant role, and with the generation of kinds of tumors and
Shift closely related.
Gram azoles is first little molecule ALK, c-of the whole world for Buddhist nun (crizotinib, English trade name Xalkori, Sai Kerui)
Met and ROS Mutiple Targets kinases inhibitor, the tumor patient that ALK kinase activity is abnormal is had aobvious for Buddhist nun by clinical confirmation gram azoles
Write clinical efficacy.Nikkei FDA Food and Drug Administration (FDA) express passway approval August 26 in 2011, gram azoles is used for for Buddhist nun
The first-line treatment medicine listing of EML4-ALK positive advanced Non-small cell lung；Obtain the approval of U.S. FDA routine in November, 2013,
For expressing the treatment of the advanced NSCLC patients of EML4-ALK fusion gene.This is lung cancer therapy field, and continue EGFR tyrosine-kinase
Another new milestone after enzyme antagonist (EGFR-TKIs).
Initially synthesis gram azoles for the route of Buddhist nun as shown in scheme 1, initially with Mitsunobu reaction build pyridine-
3 ehter bonds, then finally obtain gram through the Miyaura boration of precious metal palladium catalysis and Suzuki coupling reaction etc. 9 steps reaction
Azoles replaces Buddhist nun's racemization product, eventually passes chiral separation and obtains gram azoles of optical purity for Buddhist nun.
Scheme 1 document report gram azoles is for the synthetic route of Buddhist nun
Gram azoles reported is more for the synthetic method of Buddhist nun, but all concentrate on reacted by Mitsunobu build pyridine-
3 ehter bonds, and realized the docking of two fragments by Suzuki coupling, such as scheme 2.Mitsunobu reaction is used to carry out structure
Building-3 ehter bonds of pyridine causes organic by-products more, typically uses column chromatography for separation, commercial production to have difficulties；Use your gold
The reaction of Miyaura boration and the Suzuki coupling reaction that belong to palladium chtalyst cause the usage amount of noble metal greatly, and cost increases, environment
Pollute the most serious；And chiral separation to there is separation yield low, and produce the waste of enantiomer.Therefore, previously reported
Synthetic route and be unfavorable for industrialized production.
Scheme 2 document report gram azoles is for the synthetic route of Buddhist nun
Summary of the invention
The technical problem to be solved is to provide one to fit to overcome the problems referred to above of the prior art
Replace the synthesis technique of Buddhist nun together in industrialized preparation gram azoles, this route reaction yield is high, and optical purity is high, and organic by-products is few,
The usage amount of noble metal is substantially reduced, and meets the new concept of environmental protection.
Adopt the following technical scheme that for solving the technical problem of the present invention
A kind of compound gram azoles, for the synthesis technique of Buddhist nun, comprises the following steps:
A () makes formula (I) compound obtain formula (II) chemical combination of optical purity by the reduction reaction that hand-type amino alcohol is induced
Thing, the protection of formula (II) compound ventilating methane sulfonic acid chloride generates the compound of formula (III), formula (III) compound and 2-nitro-3-hydroxyl
Yl pyridines obtains formula (IV) compound by bimolecular nucleophilic subsititution SN2；The hand-type of its Chinese style (IV) compound by watt
You step on upset and obtain and target compounds of formula (X) identical configuration product；
B () formula (IV) compound obtains anil formula (V) compound by the reaction of Raney's nickel hydro-reduction；Formula (V)
Compound obtains 3-bromopyridine derivative formula (VI) compound, formula (VI) chemical combination by low temperature (-15～-10 DEG C) bromination reaction
Thing reacts generation formula (VII) compound under the effect of palladium catalyst with Cyanoacetyl-Cyacetazid；
C () formula (VII) compound passes through N, under conditions of N dimethylamine hydrochlorate exists, amine solution obtains amide formula (VIII)
Compound, formula (VIII) compound and 4-piperidines hydrazine formula (IX) cyclization can generate target product formula (X) compound gram azoles for Buddhist nun.
The synthetic route of the present invention is:
Further, in step (a), the optical purity of formula (II) compound depends on the optical voidness of hand-type amino alcohol
Spend, and the organic solvent used in reduction reaction is correlated with, if products therefrom is racemoid when using alcohols solvent.Above-mentioned
The chiral amino alcohol used in reaction is chirality prolinol derivative, and uses that natural L-proline is derivative to be obtained, chirality dried meat ammonia
The usage amount of the derivant of alcohol is 0.1～1.0 equivalents based on formula (I) compound mole.Above-mentioned reaction is preferably reduced
Reagent is NaBH4Or LiBH4Or KBH4Or NaCNBH3Or NaBH (OAc)3, wherein the usage amount of reducing agent is based on formula (I) chemical combination
0.1～3.0 equivalents of thing mole.In above-mentioned reaction, the preferential solvent selected is THF, may be otherwise use and can reach identical
The solvent of reduction, such as: 2-methyltetrahydrofuran, glycol dimethyl ether etc., but can not use alcohols solvent, such as: first
Alcohol, ethanol, isopropanol, the tert-butyl alcohol etc., otherwise can generate racemoid.
In step (a), the compound reaction of formula (II) compound of formula (III) can be protected by methane sulfonyl chloride
Protect rear and 2-nitro-3-pyridone generation substitution reaction, may also be herein and use other protection examinations that can reach similar effect
Agent, such as: paratoluensulfonyl chloride, 4-Nitrobenzenesulfonyl chloride etc., the most protectant usage amount is based on formula (II) chemical combination
1.0～1.5 equivalents of thing mole.The acid binding agent that above-mentioned protection reaction uses is diisopropylethylamine (DIPEA), the most also may be used
To use other alkali that can reach similar effect, such as: triethylamine, Tris(isopropylamine)., cesium carbonate, potassium carbonate, sodium carbonate, acetic acid
Potassium, sodium hydroxide, Lithium hydrate, potassium hydroxide etc., wherein the usage amount of alkali be based on formula (II) compound mole 1.0～
3.0 equivalent.
Further, SN 2-nitro-3-pyridone occurred with formula (III) compound2Substitution reaction, makes herein
Alkali be potassium carbonate, it is possible to use can reach other alkali of similar effect, such as: triethylamine, Tris(isopropylamine)., cesium carbonate,
Potassium bicarbonate, sodium carbonate, potassium acetate etc., wherein the usage amount of alkali be based on formula (III) compound mole 1.0～3.0 work as
Amount.
In above-mentioned reaction, the preferential solvent selected is isopropyl acetate, may also be use herein and can reach identical reduction
Solvent, such as: oxolane, 2-methyltetrahydrofuran, ethyl acetate, butyl acetate, DMF, isopropanol, the tert-butyl alcohol etc. are molten
Agent, wherein the usage amount of solvent is 3～20 times of volumes of weight based on formula (III) compound.
Further, in step (b), 2-nitropyridine derivatives formula (IV) can use Raney's nickel as catalysis
Agent, the nitro that reduces under atmosphere of hydrogen is amido, and catalyst Raney's nickel can realize recycling 5 batches, but catalysis activity is also
Without substantially reducing.The solvent that the reaction of this step is used is methanol, may be otherwise and uses the solvent that can reach identical reduction,
Such as: ethanol, isopropanol, normal propyl alcohol, the tert-butyl alcohol, n-butyl alcohol etc..
Note at this in step reaction, it is possible to use the reduction system of zinc powder and saturated ammonium chloride, or iron powder and hydrochloric acid body
System's reduction, but post processing is difficult, and waste residue is more.
Notice that this reaction can not use palladium carbon as catalyst, otherwise can produce a large amount of dechlorinated side product.
Further, in the bromination reaction of synthesis formula (VI) compound, bromide reagent used herein is NBS, it is possible to
It is to use other can reach the bromide reagent of same effect, such as: DBDMH, bromine, DBBA, DBI and TBAB (phenyl front three
Base ammonium bromide) etc., wherein the usage amount of bromide reagent is 1.0～3.0 equivalents based on formula (V) compound mole.
At this in reaction, the preferential solvent used is acetonitrile, may be otherwise and uses the solvent that can reach same effect, example
As: dichloromethane, chloroform, dioxane, methyl tertiary butyl ether(MTBE) and methylcyclopentyl ether etc..
At this in step reaction, when reaction temperature is the lowest, the slowest less than-30 degree reactions；When temperature is higher than 0～5 degree, bromination
Reaction selectivity can reduce, and can produce 6 replacements or 5,6 two replacement by-products.Herein optimal reaction temperature be-15～-
10 degree.
Further, in step (b), formula (VI) compound under the effect of palladium catalyst, alkali exist under conditions of with
Cyanoacetyl-Cyacetazid generation coupling reaction obtains formula (VII) compound.
Preferentially, the palladium catalyst used in above-mentioned reaction is Pd (dppf) Cl2, may be otherwise use and can reach identical
The similar catalyst of catalytic action, such as: tetrakis triphenylphosphine palladium, triphenylphosphine palladium chloride, palladium, palladium trifluoroacetate, three
Phenylphosphine palladium, double (tricyclohexyl phosphine) palladium, double (tri-butyl phosphine) palladium, double (dibenzalacetone) palladium etc., wherein palladium is urged
The usage amount of agent is based on formula (VI) compound by weight 0.1%～20%.
More preferably, the alkali used in above-mentioned coupling reaction is potassium tert-butoxide, same, and may be otherwise use can reach
To other alkali of similar effect, such as: sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, barium hydroxide, sodium hydroxide, hydrogen-oxygen
Changing potassium, triethylamine, diisopropylethylamine etc., wherein the usage amount of alkali is based on formula (II) compound mole 1.0～3.0 to work as
Amount.
Further, in step (c), Cyanoacetyl-Cyacetazid derivant formula (VII) compound aminolysis reaction in the basic conditions
Generate amide derivatives formula (VIII) compound.
At this in reaction, selecting N, N dimethylamine hydrochlorate is amine solution reagent, and in alcohols solvent, amine solution Cyanoacetyl-Cyacetazid is concurrent
Raw amido exchange reaction synthesis formula (VIII) compound, the most preferentially selecting ethanol is reaction dissolvent.May be otherwise use energy
Reach the solvent of identical exchange interaction, such as: methanol, normal propyl alcohol, isopropanol, the tert-butyl alcohol, n-butyl alcohol and n-amyl alcohol etc..
Further, in step (c), formula (VIII) compound is with the cyclization in the basic conditions of formula (IX) compound i.e.
Formula (X) compound gram azoles can be generated for Buddhist nun.
In above-mentioned reaction, the preferential solvent selected is dimethylbenzene, may be otherwise and uses the solvent that can reach similar effect,
Such as: toluene, Nitrobenzol, chlorobenzene, DMF, DMA and DMSO etc..
In above-mentioned reaction, the preferential alkali selected is triethylamine, it is possible to use can reach other alkali of similar effect, such as:
DIPEA, Tris(isopropylamine)., cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, hydroxide
Potassium, Lithium hydrate etc., the usage amount of alkali is 1.0～3.0 equivalents based on formula (VIII) compound mole the most herein.
Compared with prior art, the invention have the advantages that the provided by the present invention gram of azoles newly synthesized side for Buddhist nun
Method, uses the reaction of atom economy type, reduces environmental pollution.The chiral reduction using chirality dried meat ammonia alcohol-induced obtains high-optical-purity
Raw material, build chiral centre by SN2 substitution reaction, overcome the Mitsunobu post processing that brings of reaction and purification difficult.Adopt
Malononitrile group derivant is built, through N, the amine of N dimethylamine hydrochlorate by the coupling reaction of Cyanoacetyl-Cyacetazid with bromopyridine derivative
Solution obtains N, N-diformamide analog derivative, in this derivant, N, and N dimethylamine is anti-with hydrazine generation cyclization as easy leaving group
Answer thus build pyrazole ring, thus obtain desired final products gram azoles for Buddhist nun.Although the method uses consecutive steps, but
Every single step reaction is higher, and optical purity is high, and total recovery is the highest.The cheaper starting materials additionally used in this synthetic method is easy to get, and urges
Agent usage amount is few, and totle drilling cost is easily controllable.Operating process is easy, it is easy to controls, is suitable for industrialized production.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail.Below example is that the present invention is described
Rather than limit present disclosure by any way.
Embodiment 1
(1) preparation of formula (II) compound
Formula (I) compound (20.7g, 0.1mol), oxolane (200mL) and (S)-diphenyl dried meat is added in reaction bulb
Ammonia alcohol (2.53g, 0.01mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 1 DEG C with ice-water bath, is dividedly in some parts
NaBH4(4.5g, 0.12mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, is fallen by reactant liquor
Enter in semi-saturation aqueous ammonium chloride solution, stirring reaction 30min, it is extracted with ethyl acetate, merges organic facies, use 1N HCl successively,
5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and decompression concentrated acid is the most dry, and quantitative yield remains pale yellowish oil
Thing is directly used in next step reaction.
Column chromatography formula after purification (II) compound is colorless oil, 99.5%ee.
1H NMR(400MHz,CDCl3) δ 7.26 (dd, J=8.0,5.6Hz, 1H), 7.03 (dd, J=15.6,8.0Hz,
1H), 4.71 (q, J=6.8Hz, 1H), 4.10 (brs, 1H), 1.63 (d, J=6.6Hz, 3H).
(2) preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, addition dichloromethane (200mL), DIPEA (15.5g,
0.12mol), 10min is stirred at room temperature and is completely dissolved to solid, be cooled to 0 DEG C with ice-water bath, dropping methane sulfonyl chloride (11.5g,
0.1mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, and reactant liquor is poured into 1M KHSO4Water
In solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3Wash with saturated common salt
Washing, anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Formula can be obtained with ethyl acetate/normal hexane recrystallization
(III) compound is white solid, 26.7g, two step yields: 93%.
1H NMR(400MHz,CDCl3) δ 7.29 (dd, J=8.0,5.6Hz, 1H), 7.01 (dd, J=15.6,8.0Hz,
1H), 4.70 (q, J=6.8Hz, 1H), 3.07 (s, 3H), 1.85 (d, J=6.6Hz, 3H).
(3) preparation of formula (IV) compound
In reaction bulb, add formula (III) compound (25g, 0.087mol), add 2-nitro-3-pyridone formula
(XII) (14g, 0.1mol), K2CO3(24g, 0.174mol) and isopropyl acetate (200mL).Temperature rising reflux reaction 8h.TLC shows
Show that raw material reaction is complete.Reactant liquor being cooled to room temperature, filters, filter cake isopropyl acetate (20mL) washs.Filtrate is used successively
1N HCl, 5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and is evaporated to do, obtains yellow solid,
26.2g, yield: 91%, m.p.:96～98 DEG C.
1H NMR(400MHz,CDCl3) δ 8.05 (dd, J=7.5,1.6Hz, 1H), 7.37 (dd, J=8.8,7.5Hz,
1H), 7.31 (dd, J=8.8,4.8Hz, 1H), 7.22 (dd, J=8.4,1.6Hz, 1H), 7.03 (dd, J=8.4,4.8Hz,
1H), 6.10 (q, J=6.6Hz, 1H), 1.81 (d, J=6.6Hz, 3H).
(4) preparation of formula (V) compound
Formula (IV) compound (25g, 0.076mol), Raney's nickel (1.5g, 6wt%), ethanol is added in autoclave
(125mL).With air three times in nitrogen displacement still, then with nitrogen in hydrogen exchange still three times, and Hydrogen Vapor Pressure is controlled
1.5MPa, is warming up to 50 DEG C, and 4h is to not inhaling hydrogen in reaction.TLC display raw material reaction is complete.Reactant liquor is cooled to room temperature, filters
Reclaiming catalyst, filter cake ethanol (10mL) washs.Filtrate reduced in volume, to dry, obtains light yellow solid, 22.5g, yield:
99%, m.p.:107～110 DEG C.1H NMR(400MHz,CDCl3) δ 7.64 (d, J=4.6Hz, 1H), 7.29 (dd, J=8.8,
4.6Hz, 1H), 7.05 (m, 1H), 6.73 (d, J=7.9Hz, 1H), 6.50 (dd, J=7.9,5.4Hz, 1H), 6.04 (q, J=
6.6Hz, 1H), 1.85 (d, J=6.6Hz, 3H).
(5) preparation of formula (VI) compound
Adding formula (V) compound (20g, 0.066mol) to reaction bulb, solution is also cooled to-15 DEG C by acetonitrile (200mL).
NBS (12.3g, 0.069mol) is dissolved in acetonitrile (85mL), gained solution is slowly added dropwise such as the solution of formula (V) compound
In, maintain reacting liquid temperature less than-10 DEG C.Drip complete, continue insulation 30min.TLC display raw material reaction is complete.Will reaction
Liquid filters, and filter cake washs with cold acetonitrile (10mL).In filtrate, add dichloromethane (200mL) and temperature be warmed to room temperature,
Being subsequently adding sodium thiosulfate KOH solution washing, split-phase, lower floor's organic facies is through washing, 5%NaHCO3Solution and saturated common salt
Water washs, and anhydrous sodium sulfate is evaporated to do, obtains light yellow solid.Solids with methanol recrystallization can be obtained pale solid
Product, 21g, yield: 84%, m.p.:101～104 DEG C.
1H NMR(400MHz,CDCl3) δ 7.66 (d, J=1.4Hz, 1H), 7.36 (dd, J=1.4Hz, 1H), 7.10 (dd,
J=7.5,5.0Hz, 1H), 7.03 (dd, J=7.8,1.8Hz, 1H), 6.01 (q, J=5.8Hz, 1H), 4.84 (brs, 2H),
1.85 (d, J=6.6Hz, 3H).
(6) preparation of formula (VII) compound
Room temperature under nitrogen protect under, to reaction bulb add Cyanoacetyl-Cyacetazid (3.5g, 0.053mol), sodium tert-butoxide (12.7g,
0.13mol) with dimethylbenzene (70mL), stirring reaction 1h.Under room temperature, in reactant liquor add formula (VI) compound (20g,
0.053mol) with Pd (dppf) Cl2 (20mg).Under nitrogen protection, temperature rising reflux reaction 3h.TLC display raw material reaction is complete.Will
Reactant liquor is cooled to 0 DEG C, is slowly added dropwise 1NHCl (130mL), continues stirring 1h, filters, and filter cake is washed with cold dimethylbenzene (10mL)
Wash.Decompression removes 2/3 solvent, and cooling and stirring overnight separates out nitrogen yellow solid, and 45 DEG C of vacuum is dried to constant weight and obtains product, 17.9g,
Yield: 92.6%.
1H NMR(400MHz,CDCl3) δ 7.71 (d, J=1.4Hz, 1H), 7.31 (dd, J=7.5,5.0Hz, 1H), 7.12
(d, J=1.4Hz, 1H), 7.04 (t, J=7.8Hz, 1H), 5.55 (q, J=5.8Hz, 1H), 4.78 (s, 1H), 3.61 (s,
2H), 1.80 (d, J=5.9Hz, 3H).
(7) preparation of formula (VIII) compound
Room temperature under nitrogen protect under, to reaction bulb add formula (VII) compound (17g, 0.047mol),
N, N dimethylamine hydrochlorate (19g, 0.235mol) and 95% ethanol (170mL).Temperature rising reflux reaction 18h.TLC shows
Show that raw material reaction is complete.Reactant liquor is cooled to 0 DEG C, and a large amount of white solids separate out, and continue stirring 1h, filter, and filter cake is with cold
Ethanol (10mL) washs.45 DEG C of vacuum is dried overnight to constant weight and obtains white solid product, 20.4g, yield: 94.9%.
1H NMR(400MHz,CDCl3) δ 7.44-7.37 (m, 1H), 7.37-7.28 (m, 1H), 7.06 (q, J=7.6Hz,
1H),7.03-6.97(m,1H),5.57-5.49(m,1H),4.71-4.62(m,1H),3.65-3.55(m,2H),3.12-2.97
(m,12H),1.86-1.74(m,3H)。
(8) preparation of formula (X) compound
Under room temperature under nitrogen is protected, add formula (VIII) compound (15g, 0.033mol), formula (IX) chemical combination to reaction bulb
Thing (3.8g, 0.033mol) and dimethylbenzene (150mL), temperature rising reflux reaction 16h.TLC display raw material reaction is complete.By reactant liquor
Being cooled to room temperature, the solvent of concentrating under reduced pressure removal major part solvent to 1 times of volume remains.Acetonitrile (150mL) is added in residual liquid,
The most again it is evaporated to do, by residue acetonitrile (75mL) recrystallization, filters to obtain white solid.45 DEG C of vacuum is dried overnight
Final products gram azoles to constant weight replaces Buddhist nun, 11.9g, yield: 80.5%.M.p.:191～192 DEG C.
1H NMR(400MHz,CDCl3) δ: 7.75 (d, J=1.8Hz, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.28
(dd, J=9.0,4.9Hz, 1H), 7.04 (m, 1H), 6.85 (d, J=1.7Hz, 1H), 6.06 (q, 1H), 4.77 (br s, 2H),
4.18 (m, 1H), 3.23 (m, 2H), 2.75 (m, 2H), 2.15 (m, 2H), 1.89 (m, 2H), 1.85 (d, J=6.7Hz, 3H),
1.65(br s,1H)。
Embodiment 2
(1) preparation of formula (II) compound
Formula (I) compound (20.7g, 0.1mol), methanol (200mL) and (S)-diphenylprolinol is added in reaction bulb
(25.3g, 0.1mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 0～5 DEG C with ice-water bath, is dividedly in some parts NaBH4
(9g, 0.24mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, pours reactant liquor into semi-saturation
In aqueous ammonium chloride solution, stirring reaction 30min, it is extracted with ethyl acetate, merges organic facies, use 1N HCl, 5%NaHCO successively3
Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and decompression concentrated acid is to dry, and residual liquid obtains colorless oil, hands through column chromatography purification
Type HPLC is shown as racemization product.
Embodiment 3
(1) preparation of formula (II) compound
Formula (I) compound (20.7g, 0.1mol), 2-MeTHF (200mL) and (S)-diphenyl dried meat is added in reaction bulb
Ammonia alcohol (12.65g, 0.05mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 0 DEG C with ice-water bath, is dividedly in some parts
KBH4(13.6g, 0.36mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, is fallen by reactant liquor
Enter in semi-saturation aqueous ammonium chloride solution, stirring reaction 30min, it is extracted with ethyl acetate, merges organic facies, use 1N HCl successively,
5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and decompression concentrated acid is to dry, and residual liquid obtains colourless through column chromatography purification
Grease, hand-type HPLC is shown as 99.5%ee.
Embodiment 4
(1) preparation of formula (II) compound
Formula (I) compound (20.7g, 0.1mol) is added in reaction bulb, glycol dimethyl ether DME (200mL) and (S)-
Diphenylprolinol (2.53g, 0.01mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 4 DEG C with ice-water bath, point
Criticize and add NaCNBH3(7.54g, 0.12mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, will
Reactant liquor is poured in semi-saturation aqueous ammonium chloride solution, stirring reaction 30min, is extracted with ethyl acetate, merges organic facies, use successively
1N HCl, 5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and decompression concentrated acid is to dry, and residual liquid is through column chromatography purification
Obtaining colorless oil, hand-type HPLC is shown as 99.3%ee.
Embodiment 5
(1) preparation of formula (II) compound
Formula (I) compound (20.7g, 0.1mol) is added in reaction bulb, glycol dimethyl ether DME (200mL) and (S)-
Diphenylprolinol (2.53g, 0.01mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 5 DEG C with ice-water bath, point
Criticize and add NaBH (OAc)3(76.3g, 0.36mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete
Finishing, by reacting liquid filtering, filtrate is poured in semi-saturation aqueous ammonium chloride solution, stirring reaction 30min, is extracted with ethyl acetate, closes
And organic facies, use 1N HCl, 5%NaHCO successively3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and decompression concentrated acid is the most dry,
Residual liquid obtains colorless oil through column chromatography purification, and hand-type HPLC is shown as 99.3%ee.
Embodiment 6
The preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, addition dichloromethane (200mL), DIPEA (31g,
0.24mol), 10min is stirred at room temperature and is completely dissolved to solid, be cooled to 0 DEG C with ice-water bath, drip paratoluensulfonyl chloride
(22.2g, 0.12mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, pours reactant liquor into 1M
KHSO4In aqueous solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3With saturated food
Saline washs, and anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Can obtain with ethyl acetate/normal hexane recrystallization
Formula (XIV) compound is white solid, 37g, two step yields: 94%.
Embodiment 7
The preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, addition dichloromethane (200mL), DIPEA (15.5g,
0.12mol), 10min is stirred at room temperature and is completely dissolved to solid, be cooled to 3 DEG C with ice-water bath, drip 4-Nitrobenzenesulfonyl chloride
(22.2g, 0.1mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, pours reactant liquor into 1M
KHSO4In aqueous solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3With saturated food
Saline washs, and anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Can obtain with ethyl acetate/normal hexane recrystallization
Formula (XIV) compound is white solid, 37g, two step yields: 94%.
Embodiment 8
The preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, addition dichloromethane (200mL), TEA (36.4g,
0.36mol), 10min is stirred at room temperature and is completely dissolved to solid, be cooled to 5 DEG C with ice-water bath, dropping methylsufonyl chloride (11.5g,
0.1mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, and reactant liquor is poured into 1M KHSO4Water
In solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3Wash with saturated common salt
Washing, anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Formula can be obtained with ethyl acetate/normal hexane recrystallization
(III) compound is white solid, 26.7g, two step yields: 93%.
Embodiment 9
The preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, adds dichloromethane (200mL), Tri-n-Propylamine
(17.2g, 0.12mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 2 DEG C with ice-water bath, drips methylsufonyl chloride
(11.5g, 0.1mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, pours reactant liquor into 1M
KHSO4In aqueous solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3With saturated food
Saline washs, and anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Can obtain with ethyl acetate/normal hexane recrystallization
Formula (III) compound is white solid, 26.7g, two step yields: 93%.
Embodiment 10
The preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, adds dichloromethane (200mL), cesium carbonate
(39.1g, 0.12mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 0 DEG C with ice-water bath, drips methylsufonyl chloride
(17.3g, 0.15mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, pours reactant liquor into 1M
KHSO4In aqueous solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3With saturated food
Saline washs, and anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Can obtain with ethyl acetate/normal hexane recrystallization
Formula (III) compound is white solid, 27.3g, two step yields: 95%.
Embodiment 11
The preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, adds dichloromethane (200mL), potassium carbonate
(16.6g, 0.12mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 5 DEG C with ice-water bath, drips methylsufonyl chloride
(11.5g, 0.1mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, pours reactant liquor into 1M
KHSO4In aqueous solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3With saturated food
Saline washs, and anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Can obtain with ethyl acetate/normal hexane recrystallization
Formula (III) compound is white solid, 27g, two step yields: 95%.
Embodiment 12
The preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, adds dichloromethane (200mL), sodium carbonate
(12.7g, 0.12mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 3 DEG C with ice-water bath, drips methylsufonyl chloride
(11.5g, 0.1mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, pours reactant liquor into 1M
KHSO4In aqueous solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3With saturated food
Saline washs, and anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Can obtain with ethyl acetate/normal hexane recrystallization
Formula (III) compound is white solid, 26.1g, two step yields: 92%.
Embodiment 13
The preparation of formula (III) compound
Upper step gained formula (II) compound is joined in reaction bulb, adds dichloromethane (200mL), potassium acetate
(11.7g, 0.12mol), is stirred at room temperature 10min and is completely dissolved to solid, is cooled to 5 DEG C with ice-water bath, drips methylsufonyl chloride
(11.5g, 0.1mol).Feed complete, be warmed to room temperature and be stirred overnight.TLC display raw material reaction is complete, pours reactant liquor into 1M
KHSO4In aqueous solution, stirring reaction 10min, it is extracted with ethyl acetate, merges organic facies, use 5%NaHCO successively3With saturated food
Saline washs, and anhydrous sodium sulfate is dried, and is evaporated to do, and obtains khaki solid.Can obtain with ethyl acetate/normal hexane recrystallization
Formula (III) compound is white solid, 25.5g, two step yields: 89%.
Embodiment 14
The preparation of formula (IV) compound
In reaction bulb, add formula (III) compound (25g, 0.087mol), add 2-nitro-3-pyridone formula
(XII) (14g, 0.1mol), K2CO3(36.3g, 0.26mol) and ethyl acetate (500mL).Temperature rising reflux reaction 4h.TLC shows
Raw material reaction is complete.Reactant liquor being cooled to room temperature, filters, filter cake ethyl acetate (20mL) is washed.Filtrate uses 1N successively
HCl, 5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and is evaporated to do, and obtains yellow solid, 25.3g, receives
Rate: 87.8%, m.p.:96～98 DEG C.
Embodiment 15
The preparation of formula (IV) compound
In reaction bulb, add formula (III) compound (25g, 0.087mol), add 2-nitro-3-pyridone formula
(XII) (14g, 0.1mol), Na2CO3(46.1g, 0.44mol) and butyl acetate (400mL).Temperature rising reflux reaction 4h.TLC shows
Show that raw material reaction is complete.Reactant liquor being cooled to room temperature, filters, filter cake butyl acetate (20mL) washs.Filtrate uses 1N successively
HCl, 5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and is evaporated to do, and obtains yellow solid, 24.2g, receives
Rate: 87.8%, m.p.:96～98 DEG C.
Embodiment 16
The preparation of formula (IV) compound
In reaction bulb, add formula (III) compound (25g, 0.087mol), add 2-nitro-3-pyridone formula
(XII) (14g, 0.1mol), DIPEA (33.7g, 0.26mol) and 2-MeTHF (300mL).Temperature rising reflux reaction 4h.TLC shows
Raw material reaction is complete.Reactant liquor being cooled to room temperature, filters, filter cake 2-MeTHF (20mL) washs.Filtrate uses 1N successively
HCl, 5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and is evaporated to do, and obtains yellow solid, 26.5g, receives
Rate: 92.1%, m.p.:96～98 DEG C.
Embodiment 17
The preparation of formula (IV) compound
In reaction bulb, add formula (III) compound (25g, 0.087mol), add 2-nitro-3-pyridone formula
(XII) (14g, 0.1mol), TEA (17.6g, 0.174mol) and THF (200mL).Temperature rising reflux reaction 4h.TLC shows raw material
React complete.Reactant liquor being cooled to room temperature, filters, filter cake ethyl acetate (80mL) is washed.Filtrate uses 1N HCl successively,
5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and is evaporated to do, and obtains yellow solid, 24.9g, yield:
86.5%, m.p.:96～98 DEG C.
Embodiment 18
The preparation of formula (IV) compound
In reaction bulb, add formula (III) compound (25g, 0.087mol), add 2-nitro-3-pyridone formula
(XII) (14g, 0.1mol), K2CO3(24g, 0.174mol) and DMF (150mL).It is warming up to 100 degree, reacts 4h.TLC shows former
Material reaction is complete.Reactant liquor being cooled to room temperature, filters, filter cake DMF (10mL) washs.Filtrate pours frozen water (300mL) into, has
A large amount of yellow mercury oxides separate out, and room temperature continues stirring 1h, filters, and filter cake clear water (20mL) washs, and 50 degree of vacuum drying 24h obtain yellow
Color solid product, 26g, yield: 90%, m.p.:95～97 DEG C.
Embodiment 19
The preparation of formula (IV) compound
In reaction bulb, add formula (III) compound (25g, 0.087mol), add 2-nitro-3-pyridone formula
(XII) (14g, 0.1mol), DIPEA (22.4g, 0.174mol) and isopropanol (200mL).Temperature rising reflux reaction 4h.TLC shows
Raw material reaction is complete.Reactant liquor being cooled to room temperature, filters, filter cake isopropanol (20mL) washs.Filtrate reduced in volume is to greatly
Partial solvent steams, and residual liquid ethyl acetate (100mL) dilutes, and uses 1N HCl, 5%NaHCO successively3Wash with saturated common salt
Washing, anhydrous sodium sulfate is dried, and is evaporated to do, and obtains yellow solid, 26.2g, yield: 91%, m.p.:96～98 DEG C.
Embodiment 20
The preparation of formula (IV) compound
In reaction bulb, add formula (III) compound (25g, 0.087mol), add 2-nitro-3-pyridone formula
(XII) (14g, 0.1mol), K2CO3(18.5g, 0.174mol) and the tert-butyl alcohol (200mL).Temperature rising reflux reaction 4h.TLC shows
Raw material reaction is complete.Reactant liquor being cooled to room temperature, filters, filter cake ethyl acetate (100mL) is washed.Filtrate uses 1N successively
HCl, 5%NaHCO3Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and is evaporated to do, and obtains yellow solid, 24.2g, receives
Rate: 87.8%, m.p.:96～98 DEG C.
Embodiment 21
The preparation of formula (VII) compound
Room temperature under nitrogen protect under, to reaction bulb add Cyanoacetyl-Cyacetazid (3.5g, 0.053mol), potassium tert-butoxide (14.6g,
0.13mol) with dimethylbenzene (70mL), stirring reaction 1h.Under room temperature, in reactant liquor add formula (VI) compound (20g,
0.053mol) with Pd (PPh3) 2Cl2 (4g).Under nitrogen protection, temperature rising reflux reaction 3h.TLC display raw material reaction is complete.Will
Reactant liquor is cooled to 0 DEG C, is slowly added dropwise 1N HCl (130mL), continues stirring 1h, filters, and filter cake is with cold dimethylbenzene (10mL)
Washing.Decompression removes 2/3 solvent, and cooling and stirring overnight separates out nitrogen yellow solid, and 45 DEG C of vacuum is dried to constant weight and obtains product,
17.9g, yield: 92.6%.
Embodiment 22
The preparation of formula (VII) compound
Under room temperature under nitrogen is protected, add Cyanoacetyl-Cyacetazid (3.5g, 0.053mol), Cs to reaction bulb2CO3(42.3g,
0.13mol) with dimethylbenzene (70mL), stirring reaction 1h.Under room temperature, in reactant liquor add formula (VI) compound (20g,
0.053mol) with Pd (PPh3) 4 (1g).Under nitrogen protection, temperature rising reflux reaction 3h.TLC display raw material reaction is complete.Will reaction
Liquid is cooled to 0 DEG C, is slowly added dropwise 1N HCl (130mL), continues stirring 1h, filters, and filter cake washs with cold dimethylbenzene (10mL).
Decompression removes 2/3 solvent, and cooling and stirring overnight separates out nitrogen yellow solid, and 45 DEG C of vacuum is dried and obtains product, 18.2g to constant weight, receives
Rate: 94.3%.
Embodiment 23
The preparation of formula (VII) compound
Under room temperature under nitrogen is protected, add Cyanoacetyl-Cyacetazid (3.5g, 0.053mol), Na to reaction bulb2CO3(13.8g,
0.13mol) with dimethylbenzene (70mL), stirring reaction 1h.Under room temperature, in reactant liquor add formula (VI) compound (20g,
0.053mol) with Pd (dppf) Cl2 (2g).Under nitrogen protection, temperature rising reflux reaction 3h.TLC display raw material reaction is complete.Will be anti-
Answering liquid to be cooled to 0 DEG C, be slowly added dropwise 1N HCl (130mL), continue stirring 1h, filter, filter cake is washed with cold dimethylbenzene (10mL)
Wash.Decompression removes 2/3 solvent, and cooling and stirring overnight separates out nitrogen yellow solid, and 45 DEG C of vacuum is dried to constant weight and obtains product, 15.3g,
Yield: 78.9%.
Embodiment 24
The preparation of formula (VII) compound
Under room temperature under nitrogen is protected, add Cyanoacetyl-Cyacetazid (3.5g, 0.053mol), K to reaction bulb2CO3(18g, 0.13mol)
With dimethylbenzene (70mL), stirring reaction 1h.Under room temperature, in reactant liquor, add formula (VI) compound (20g, 0.053mol) and Pd
(dppf)Cl2(100mg).Under nitrogen protection, temperature rising reflux reaction 3h.TLC display raw material reaction is complete.Reactant liquor is cooled to
0 DEG C, being slowly added dropwise 1N HCl (130mL), continue stirring 1h, filter, filter cake washs with cold dimethylbenzene (10mL).Decompression removes
2/3 solvent, cooling and stirring overnight separates out nitrogen yellow solid, and 45 DEG C of vacuum is dried to constant weight and obtains product, 16.1g, yield: 83%.
Embodiment 25
The preparation of formula (VII) compound
Room temperature under nitrogen protect under, to reaction bulb add Cyanoacetyl-Cyacetazid (3.5g, 0.053mol), DIPEA (16.8g,
0.13mol) with dimethylbenzene (70mL), stirring reaction 1h.Under room temperature, in reactant liquor add formula (VI) compound (20g,
0.053mol) with Pd (dppf) Cl2 (500mg).Under nitrogen protection, temperature rising reflux reaction 3h.TLC display raw material reaction is complete.
Reactant liquor being cooled to 0 DEG C, is slowly added dropwise 1N HCl (130mL), continue stirring 1h, filter, filter cake is with cold dimethylbenzene
(10mL) washing.Decompression removes 2/3 solvent, and cooling and stirring overnight separates out nitrogen yellow solid, and 45 DEG C of vacuum is dried to constant weight and must produce
Product, 16.3g, yield: 84%.
Embodiment 26
The preparation of formula (VII) compound
Under room temperature under nitrogen is protected, add Cyanoacetyl-Cyacetazid (3.5g, 0.053mol), TEA (13.2g, 0.13mol) to reaction bulb
With dimethylbenzene (70mL), stirring reaction 1h.Under room temperature, in reactant liquor, add formula (VI) compound (20g, 0.053mol) and Pd
(dppf)Cl2(200mg).Under nitrogen protection, temperature rising reflux reaction 3h.TLC display raw material reaction is complete.Reactant liquor is cooled to
0 DEG C, being slowly added dropwise 1N HCl (130mL), continue stirring 1h, filter, filter cake washs with cold dimethylbenzene (10mL).Decompression removes
2/3 solvent, cooling and stirring overnight separates out nitrogen yellow solid, and 45 DEG C of vacuum is dried to constant weight and obtains product, 15.1g, yield: 78%.
Claims (10)
1. a compound gram azoles is for the synthesis technique of Buddhist nun, it is characterised in that comprise the following steps:
A () makes formula (I) compound obtain the formula (II) compound of optical purity, formula by the reduction reaction that hand-type amino alcohol is induced
(II) compound generates the compound of formula (III), formula (III) compound and 2-nitro-3-hydroxyl by methane sulfonyl chloride protection
Pyridine obtains formula (IV) compound by bimolecular nucleophilic subsititution SN2, and the hand-type of formula (IV) compound is turned over by Walden
Turn and obtain and target compounds of formula (X) identical configuration product；
B () formula (IV) compound obtains anil formula V compound by the reaction of Raney's nickel hydro-reduction；Formula V chemical combination
Thing is-15~Obtaining 3-bromopyridine derivative formula (VI) compound by bromination reaction at-10 DEG C, formula (VI) compound is at palladium
Generation formula (VII) compound is reacted under the effect of catalyst and under conditions of alkali existence with Cyanoacetyl-Cyacetazid；
C () formula (VII) compound passes through N, under conditions of N dimethylamine hydrochlorate exists, amine solution obtains amide formula (VIII) chemical combination
Thing, formula (VIII) compound and 4-piperidines hydrazine formula (IX) compound cyclization generate target product formula (X) compound gram azoles for Buddhist nun.
The compound gram azoles stated the most according to claim 1 is for the synthesis technique of Buddhist nun, it is characterised in that: described step (a)
The solvent of reduction reaction of middle hand-type amino alcohol induction is tetrahydrofuran THF or 2-methyltetrahydrofuran or glycol dimethyl ether,
Also original reagent is NaBH4Or KBH4Or NaCNBH3Or NaBH (OAc)3, wherein the usage amount of reducing agent is based on formula (I) chemical combination
The 0.1-3.0 equivalent of thing mole.
The compound gram azoles stated the most according to claim 1 and 2 is for the synthesis technique of Buddhist nun, it is characterised in that: described step
A in (), hand-type amino alcohol is hand-type prolinol derivative, use natural L-proline to derive and obtain, the use of chirality dried meat ammonia alcohol
Amount is the 0.1-1.0 equivalent of formula (I) compound mole.
Compound gram azoles the most according to claim 1 and 2 is for the synthesis technique of Buddhist nun, it is characterised in that: in described step (a)
By toluene sulfochloride or the easy leaving group of 4-Nitrobenzenesulfonyl chloride in the compound reaction of formula (II) compound of formula (III)
Protection, the most protectant usage amount is the 1.0-1.5 equivalent of formula (II) compound mole.
Compound gram azoles the most according to claim 1 and 2 is for the synthesis technique of Buddhist nun, it is characterised in that: in described step (a)
During in the compound reaction of formula (II) compound of formula (III), easily leaving group is protected, acid binding agent is diisopropylethylamine
DIPEA or triethylamine or Tri-n-Propylamine or cesium carbonate or potassium carbonate or sodium carbonate or potassium acetate, the usage amount of alkali is the most herein
The 1.0-3.0 equivalent of formula (II) compound mole.
Compound gram azoles the most according to claim 1 and 2 is for the synthesis technique of Buddhist nun, it is characterised in that: in described step (a)
The SN that 2-nitro-3-pyridone occurs with formula (III) compound2The alkali used in substitution reaction is potassium carbonate or triethylamine,
Diisopropyl ethyl amine or cesium carbonate or sodium carbonate, the usage amount of alkali is that the 1.0-5.0 of formula (III) compound mole works as the most herein
Amount.
Compound gram azoles the most according to claim 1 and 2 is for the synthesis technique of Buddhist nun, it is characterised in that: in described step (a)
The SN that 2-nitro-3-pyridone occurs with formula (III) compound2The solvent used in substitution reaction is isopropyl acetate or four
Hydrogen furan or 2-methyltetrahydrofuran or ethyl acetate or butyl acetate or DMF or isopropanol or the tert-butyl alcohol, solvent the most herein
The 3-20 times of volume that usage amount is formula (III) compound.
Compound gram azoles the most according to claim 1 and 2 is for the synthesis technique of Buddhist nun, it is characterised in that: in described step (b)
Palladium catalyst triphenylphosphine palladium chloride, tetrakis triphenylphosphine palladium, Pd (dppf) Cl2, wherein the use weight of palladium catalyst is formula
(VI) the 0.1%-20% of compound by weight.
Compound gram azoles the most according to claim 1 and 2 is for the synthesis technique of Buddhist nun, it is characterised in that: in described step (b)
Alkali is potassium tert-butoxide or sodium tert-butoxide or cesium carbonate or potassium carbonate or sodium carbonate or triethylamine or diisopropylethylamine, the most herein
The usage amount of alkali is the 1.0-3.0 equivalent of formula (III) compound mole.
Compound gram azoles the most according to claim 1 is for the synthesis technique of Buddhist nun, it is characterised in that: synthetic route is
。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107417603A (en) * | 2017-05-17 | 2017-12-01 | 江苏斯威森生物医药工程研究中心有限公司 | A kind of Crizotinib intermediate preparation method |
| CN108191833A (en) * | 2018-01-17 | 2018-06-22 | 浙江树人学院 | Gram azoles is for Buddhist nun's derivative and its preparation method and application |
| CN112125841A (en) * | 2020-10-23 | 2020-12-25 | 南京安淮创新药物研究院有限公司 | Novel synthesis method of crizotinib intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584795A (en) * | 2012-01-13 | 2012-07-18 | 唐虹 | Preparing method of crizotinib |
| CN103992307A (en) * | 2013-02-16 | 2014-08-20 | 浙江九洲药物科技有限公司 | Preparation method for crizotinib |
| CN104402679A (en) * | 2014-11-24 | 2015-03-11 | 苏州乔纳森新材料科技有限公司 | Synthetic method for crizotinib intermediate |
-
2016
- 2016-05-31 CN CN201610375575.0A patent/CN105924431B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584795A (en) * | 2012-01-13 | 2012-07-18 | 唐虹 | Preparing method of crizotinib |
| CN103992307A (en) * | 2013-02-16 | 2014-08-20 | 浙江九洲药物科技有限公司 | Preparation method for crizotinib |
| CN104402679A (en) * | 2014-11-24 | 2015-03-11 | 苏州乔纳森新材料科技有限公司 | Synthetic method for crizotinib intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 张广艳 等: "克里唑替尼的合成工艺研究", 《中国药物化学杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107417603A (en) * | 2017-05-17 | 2017-12-01 | 江苏斯威森生物医药工程研究中心有限公司 | A kind of Crizotinib intermediate preparation method |
| CN107417603B (en) * | 2017-05-17 | 2020-08-11 | 张家港威胜生物医药有限公司 | Preparation method of crizotinib intermediate |
| CN108191833A (en) * | 2018-01-17 | 2018-06-22 | 浙江树人学院 | Gram azoles is for Buddhist nun's derivative and its preparation method and application |
| CN112125841A (en) * | 2020-10-23 | 2020-12-25 | 南京安淮创新药物研究院有限公司 | Novel synthesis method of crizotinib intermediate |
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