CN103819396A - Synthesis method of chiral 1-(3,5-dichloropyridine-4-yl)-ethanol - Google Patents
Synthesis method of chiral 1-(3,5-dichloropyridine-4-yl)-ethanol Download PDFInfo
- Publication number
- CN103819396A CN103819396A CN201410064211.1A CN201410064211A CN103819396A CN 103819396 A CN103819396 A CN 103819396A CN 201410064211 A CN201410064211 A CN 201410064211A CN 103819396 A CN103819396 A CN 103819396A
- Authority
- CN
- China
- Prior art keywords
- dichloropyridine
- ethanol
- reaction
- ethyl ketone
- iii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an asymmetric synthesis method of 1-(3,5-dichloropyridine-4-yl)-ethanol. The asymmetric synthesis method comprises the following steps: (A) under an action of lithium amide, carrying out a reaction of 3,5-dichloropyridine (I) with acetaldehyde to generate (+/-)-1-(3,5-dichloropyridine-4-yl)-ethanol (II); (B) under an action of an oxidant, allowing (+/-)-1-(3,5-dichloropyridine-4-yl)-ethanol (II) to generate 1-(3,5-dichloropyridine-4-yl)-ethyl ketone (III); and (C) in the presence of a chiral ligand, carrying out a reaction of 1-(3,5-dichloropyridine-4-yl)-ethyl ketone with a borane reagent, and thus obtaining the 1-(3,5-dichloropyridine-4-yl)-ethanol (IV) having a single optical isomer. Compared with traditional chiral column separation of (+/-)-1-(3,5-dichloropyridine-4-yl)-ethanol, the method has the prominent advantages that: (1) the reactions are simple, the operation is easy, the total yield is high, and the optical purity is more than 98%; (2) the industrial preparation period is shortened obviously, and equipment requirements are low; and (3) the preparation cost is low, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to medicine intermediate field, relate to a kind of 1-(3 of chirality, 5-dichloropyridine-4-yl)-ethanol synthetic method and application thereof.
Background technology
Fibroblast growth factor acceptor (FGFR) belongs to receptor type protein tyrosine kinase, and this family mainly comprises FGFR1, FGFR2, FGFR3 and tetra-members of FGFR4.FGFR participates in regulating multiple processes such as cell proliferation, apoptosis, migration, new vessel generation.Because effect is extensive, FGFR and other RTK are subject to strict regulation and control under normal circumstances.In tumour, as in mammary cancer, bladder cancer, prostate cancer etc., FGFR activated mutant or ligand/receptor are crossed to express and are caused its sustained activation, not only closely related with the generation of tumour, development, poor prognosis etc., and also play a significant role in the process such as invasion and attack and transfer of tumor angiogenesis, tumour.Therefore, FGFR is acknowledged as antitumor important target spot, and the research and development of FGFR micromolecular inhibitor progressively receive increasing concern.FGFR inhibitor has been reported as antineoplastic compound, as WO 2002022598.Wherein LY2874455 is the inhibitor of a species specificity FGFRs, has entered at present the second phase clinical, and prospect is very good.
S-1-(3,5-dichloropyridine-4-yl) ethanol is the important intermediate of a kind of synthetic FGFR inhibitor LY2874455, and bibliographical information before adopts HPLC chiral column to separate raceme to obtain single chiral isomer S-1-(3,5-dichloropyridine-4-yl) ethanol, and only carry out the evaluation of optical isomer absolute configuration by vibration circular dichroism spectrum and infrared spectra, as CN102421769A.Its method yield is low, and separation costs is high, and preparation cycle is long, cannot carry out suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of dissymmetric synthesis of high yield, for the preparation of thering is optically active 1-(3,5-dichloropyridine-4-yl) ethanol, the method step is short, and preparation is simple, and equipment requirements is low, yield and optical purity are all very high, are to be applicable to industrial method.
The 1-(3 of a kind of chirality provided by the invention, 5-dichloropyridine-4-yl) synthetic method of-ethanol and sulphonate, its feature comprises the following steps:
A. 3,5-dichloropyridine (I) reacts generation (±)-1-(3 under the effect of amido lithium with acetaldehyde, 5-dichloropyridine-4-yl)-ethanol (II);
B. (±)-1-(3,5-dichloropyridine-4-yl)-ethanol (II) generates 1-(3,5-dichloropyridine-4-yl under the effect of oxygenant)-ethyl ketone (III);
C. 1-(3,5-dichloropyridine-4-yl)-ethyl ketone (III) reacts with borane reagent under corresponding chiral ligand exists, and makes the 1-(3 of single optical isomer, 5-dichloropyridine-4-yl)-ethanol (IV);
As optimal way, in described step a, the solvent of use in tetrahydrofuran (THF), ether, normal hexane, hexanaphthene one or more;
As optimal way, in described step a, the amido lithium of use is lithium diisopropyl amido;
As optimal way, in described step a, the mol ratio of 3,5-dichloropyridine and acetaldehyde is: 1:1 ~ 10; Temperature of reaction is :-78
oc ~ 0
oc; Reaction times: 1 ~ 12 hour;
As optimal way, in described step b, the solvent using is methylene dichloride or acetonitrile; Oxygenant be in Pyridinium chlorochromate on silica gel, pyridinium dichromate, Jones reagent (Jones), Dai Si-Martin reagent (Dess-Martin) one or more; (±)-1-(3,5-dichloropyridine-4-yl)-ethanol (II) with the mol ratio of oxygenant is: 1:1 ~ 5; Temperature of reaction is :-20
oc ~ 60
oc; Reaction times is: 1 ~ 12 hour;
As optimal way, in described step c, the solvent using in methylene dichloride, tetrahydrofuran (THF), ether, dioxane one or more; Chiral ligand is selected from: S-2-methyl-CBS-oxazaborolidine or R-2-methyl-CBS-oxazaborolidine; Borane reagent is selected from: in borine dimethyl sulphide, borine tetrahydrofuran (THF), borine pyridine one or more;
As optimal way, in described step c, 1-(3,5-dichloropyridine-4-yl) mol ratio of-ethyl ketone (III), chiral ligand and borane reagent is: 1:0.1-1:1-10,
Further preferably, 1-(3,5-dichloropyridine-4-yl) mol ratio of-ethyl ketone (III), chiral ligand and borane reagent is: 1:0.2:5; Temperature of reaction is-40
oc ~ 60
oc, preferred-10
oc; Reaction times is 1 ~ 12 hour;
At the beginning of preparation, we intend adopting the method splitting to obtain 1-(3,5-dichloropyridine-4-yl) individual isomer of-ethanol, and attempted multiple chiral resolving agent its enantiomer is carried out to chiral separation, but all do not obtain satisfied result.Adopted afterwards the method for direct its corresponding ketone of asymmetric reduction, and attempt multiple chiral ligand and reductive condition, finally obtain best result with 2-methyl-CBS-oxazaborolidine of chirality, ee>98%, and two-step reaction total recovery is greater than 80%, be obviously better than the method for resolution, and operation is simple, equipment cost is low, very applicable industrial production.
Specific embodiment
Comparative example below and embodiment are described further technical scheme of the present invention, but think that scarcely these comparative examples and embodiment have limited the present invention.
Embodiment 1
1-(3,5-dichloropyridine-4-yl) preparation of ethanol (II)
Diisopropylamine (DIPA, 13.2ml, 94.60mmol) is dissolved in to anhydrous tetrahydro furan (THF, 50ml), cooling at-78 ℃, slowly drip n-Butyl Lithium (1.6M hexane solution, 50ml, 81.08mmol), reaction solution is muddy gradually, after 1h, drips and finishes, after cooling 20min, drip 3, the THF(30ml of 5-dichloropyridine (I) (10g, 67.57mmol)) solution, reaction solution is yellow muddy shape.Be added dropwise to complete rear cooling 30min, drip the THF(20ml of the solution metaldehyde (8.93g, 11.4ml, 135.14mmol) of prior precooling) solution, reaction solution becomes clarification.After-78 ℃ of reaction 3h, drip saturated aqueous ammonium chloride solution (50ml) stopped reaction, under stirring at room temperature, spend the night.With methyl tertiary butyl ether (MTBE, 200ml) and saturated ammonium chloride solution (500ml) dilute reaction solution, separate organic phase, MTBE washing 3 times, merges organic phase saturated common salt water washing for water layer, and dried over sodium sulfate concentrates and to obtain red oil.By silica gel column chromatography (sherwood oil: ethyl acetate=20:1) purifying, obtain white solid 8.50g, yield 65%; Mp:61-64 ℃; ESI-MS (m/z): 214[M+Na]
+
Embodiment 2
The preparation of the chloro-4-acetylpyridine of 3,5-bis-(III)
By 1-(3,5-dichloropyridine-4-yl) ethanol (II) (6g, 31.24mmol) is dissolved in methylene dichloride (DCM, 50ml), adds pyridinium chlorochromate drone salt (PCC, 10.1g, 46.86mmol), room temperature reaction 10h in 10min in batches.Remove by filter insolubles, DCM washing 3 times, merges organic layer for filter residue, the concentrated crude product that to obtain.By silica gel column chromatography (sherwood oil: ethyl acetate=20:1) purifying, obtain colourless muddy oily matter 5.10g; Yield 85%;
1h-NMR (CDCl
3, 400MHz) and δ (ppm): 2.58 (s, 3H), 8.53 (s, 2H); ESI-MS (m/z): 212[M+Na]
+
Embodiment 3
(R)-1-(3,5-dichloropyridine-4-yl) ethanol (IV)
By (S)-2-methyl-CBS-oxazaborolidine (1M toluene solution, 5.3ml, 5.26mmol) and borine dimethyl sulphide complex compound (BH
3-DMS, 10M dimethyl sulphide solution, 13.2ml, 131.5mmol) be dissolved in anhydrous methylene chloride (DCM, 100ml)-10
ounder C, stir 10min, slowly drip the DCM(30ml of the chloro-4-acetylpyridine of 3,5-bis-(III) (5g, 26.3mmol)) solution, drips and finishes ,-10
oafter C reaction 12h, slowly rise to room temperature, slowly splash into methyl alcohol quencher reaction.Drip and finish, 70
oc backflow 3h.Reaction solution is concentrated to obtain to crude product, by silica gel column chromatography (sherwood oil: ethyl acetate=20:1) purifying, obtain colorless oil 4.87g; Yield 96%, ee value 98.14% (Daicel Chiralpak AD-H, normal hexane: Virahol=95:5); [α]
d=11.55 (c=0.3292, MeOH);
1h-NMR (CDCl
3, 400MHz) and δ (ppm): 1.56 (d,
j=6.8Hz, 3H), 3.56 (brs, 1H), 5.47 (q,
j=6.8Hz, 1H), 8.34 (s, 2H); ESI-MS (m/z): 214[M+Na]
+
Embodiment 4
(R)-1-(3,5-dichloropyridine-4-yl) ethyl methane sulfonate ester (V)
By (R)-1-(3,5-dichloropyridine-4-yl) ethanol (IV) (4.5g, 23.43mmol) and triethylamine (8.54g, 84.35mmol) be dissolved in anhydrous methylene chloride (100ml), agitation and dropping methane sulfonyl chloride (3.22g, 28.12mmol) under ice bath.Drip and finish, room temperature reaction, TLC detection reaction to raw material disappears, and by reaction solution impouring saturated sodium bicarbonate solution, separates organic layer, methylene dichloride returns extraction water layer, merge organic layer, after saturated common salt water washing organic layer 3 times, after anhydrous sodium sulfate drying, underpressure distillation is removed methylene dichloride by silica gel column chromatography (sherwood oil: ethyl acetate=20:1) purifying, obtain pure white crystal 5.78g, yield 91%.And determine its absolute configuration by single crystal diffraction.
1h-NMR (CDCl
3, 400MHz) and δ (ppm): 8.53 (s, 2H), 6.37 (q,
j=6.8Hz, 1H), 2.98 (s, 3H), 1.82 (d,
j=6.8Hz, 3H); ESI-MS (m/z): 292[M+Na]
+. (R)-1-(3,5-dichloropyridine-4-yl) ethyl methane sulfonate ester single crystal diffraction figure is shown in Fig. 1.
accompanying drawing explanation
fig. 1 represents (R)-1-(3,5-dichloropyridine-4-yl) ethyl methane sulfonate ester single crystal diffraction figure;
Embodiment 5
(S)-1-(3,5-dichloropyridine-4-yl) ethanol (VI)
By (R)-2-methyl-CBS-oxazaborolidine (1M toluene solution, 3.2ml, 3.15mmol) and borine dimethyl sulphide complex compound (BH
3-DMS, 10M dimethyl sulphide solution, 7.9ml, 78.9mmol) be dissolved in anhydrous methylene chloride (DCM, 75ml)-10
ounder C, stir 10min, slowly drip the DCM(15ml of the chloro-4-acetylpyridine of 3,5-bis-(III) (3g, 15.8mmol)) solution, drips and finishes ,-10
oafter C reaction 10h, slowly rise to room temperature, slowly splash into methyl alcohol quencher reaction.Drip and finish, 70
oc backflow 1.5h.Reaction solution is concentrated to obtain to crude product, by silica gel column chromatography (sherwood oil: ethyl acetate=20:1) purifying, obtain colorless oil 2.83g; Yield 97%, ee value 98.71% (Daicel Chiralpak AD-H, normal hexane: Virahol=95:5); [α]
d=-11.67 (c=0.3314, MeOH); ESI-MS (m/z): 214[M+Na]
+
Embodiment 6 (S)-1-(3,5-dichloropyridine-4-yl) ethyl methane sulfonate ester (VII)
By (S)-1-(3,5-dichloropyridine-4-yl) ethanol (VI) (1.8g, 9.37mmol) and triethylamine (3.42g, 50.61mmol) be dissolved in anhydrous methylene chloride (50ml), agitation and dropping methane sulfonyl chloride (1.29g, 11.25mmol) under ice bath.Drip and finish, room temperature reaction, TLC detection reaction to raw material disappears, and by reaction solution impouring saturated sodium bicarbonate solution, separates organic layer, methylene dichloride returns extraction water layer, merge organic layer, after saturated common salt water washing organic layer 3 times, after anhydrous sodium sulfate drying, underpressure distillation is removed methylene dichloride by silica gel column chromatography (sherwood oil: ethyl acetate=20:1) purifying, obtain pure white crystal 2.15g, yield 93%; ESI-MS (m/z): 292[M+Na]
+.
Claims (4)
1. an optically pure 1-(3,5-dichloropyridine-4-yl) synthetic method of-ethanol, its feature comprises following step:
(a) 3,5-dichloropyridine (I) reacts generation (±)-1-(3 under the effect of amido lithium with acetaldehyde, 5-dichloropyridine-4-yl)-ethanol (II);
(b) (±)-1-(3,5-dichloropyridine-4-yl)-ethanol (II) generates 1-(3,5-dichloropyridine-4-yl under the effect of oxygenant)-ethyl ketone (III);
(c) 1-(3,5-dichloropyridine-4-yl)-ethyl ketone (III) reacts with borane reagent under corresponding chiral ligand exists, and makes the 1-(3 of single optical isomer, 5-dichloropyridine-4-yl)-ethanol (IV);
。
2. a kind of optically pure 1-(3 according to claim 1,5-dichloropyridine-4-yl) synthetic method of-ethanol, it is characterized in that: in described step a, the solvent of use in tetrahydrofuran (THF), ether, normal hexane, hexanaphthene one or more; Amido lithium is lithium diisopropyl amido; The mol ratio of 3,5-dichloropyridine and acetaldehyde is: 1:1 ~ 10; Temperature of reaction is :-78
oc ~ 0
oc; Reaction times: 1 ~ 12 hour.
3. a kind of optically pure 1-(3 according to claim 1,5-dichloropyridine-4-yl) synthetic method of-ethanol, it is characterized in that: in described step b, the solvent using is methylene dichloride or acetonitrile; Oxygenant be in Pyridinium chlorochromate on silica gel, pyridinium dichromate, Jones reagent (Jones), Dai Si-Martin reagent (Dess-Martin) one or more; (±)-1-(3,5-dichloropyridine-4-yl)-ethanol (II) with the mol ratio of oxygenant is: 1:1 ~ 5; Temperature of reaction is :-20
oc ~ 60
oc; Reaction times is: 1 ~ 12 hour.
4. a kind of optically pure 1-(3 according to claim 1,5-dichloropyridine-4-yl) synthetic method of-ethanol, it is characterized in that: in described step c, the solvent using in methylene dichloride, tetrahydrofuran (THF), ether, dioxane one or more; Chiral ligand is selected from: S-2-methyl-CBS-oxazaborolidine or R-2-methyl-CBS-oxazaborolidine; Borane reagent is selected from: in borine dimethyl sulphide, borine tetrahydrofuran (THF), borine pyridine one or more; 1-(3,5-dichloropyridine-4-yl) mol ratio of-ethyl ketone (III), chiral ligand and borane reagent is: 1:0.1-1:1-10, preferably 1:0.2:5; Temperature of reaction is-40
oc ~ 60
oc, preferred-10
oc; Reaction times is 1 ~ 12 hour.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410064211.1A CN103819396B (en) | 2014-02-26 | 2014-02-26 | A kind of 1-(3,5-dichloropyridine-4-base of chirality) synthetic method of-ethanol |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410064211.1A CN103819396B (en) | 2014-02-26 | 2014-02-26 | A kind of 1-(3,5-dichloropyridine-4-base of chirality) synthetic method of-ethanol |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103819396A true CN103819396A (en) | 2014-05-28 |
CN103819396B CN103819396B (en) | 2016-06-15 |
Family
ID=50754732
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410064211.1A Expired - Fee Related CN103819396B (en) | 2014-02-26 | 2014-02-26 | A kind of 1-(3,5-dichloropyridine-4-base of chirality) synthetic method of-ethanol |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103819396B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111484393A (en) * | 2019-01-28 | 2020-08-04 | 上海茂晟康慧科技有限公司 | Preparation method of cis, cis-3, 5-dimethyl-1-cyclohexanol |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101274938A (en) * | 2007-03-27 | 2008-10-01 | 上海威智医药科技有限公司 | Preparation for (S) or (R)-2-methyl-CBS-chiral oxazaborolidine and toluene solution thereof |
WO2010129509A1 (en) * | 2009-05-07 | 2010-11-11 | Eli Lilly And Company | Vinyl indazolyl compounds |
CN102971306A (en) * | 2010-05-14 | 2013-03-13 | 医疗技术研究局 | Pyrazolopyridines as inhibitors of the kinase LRRK2 |
CN103153983A (en) * | 2010-10-05 | 2013-06-12 | 伊莱利利公司 | Crystalline (r) - (e) -2- (4- (2- (5- (1- (3, 5 -dichloropyridin-4 -yl) ethoxy) - 1H - indazol - 3 - yl) vinyl) -1 H- pyrazol- 1 -yl) ethanol and its use as FGFR inhibitor |
-
2014
- 2014-02-26 CN CN201410064211.1A patent/CN103819396B/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101274938A (en) * | 2007-03-27 | 2008-10-01 | 上海威智医药科技有限公司 | Preparation for (S) or (R)-2-methyl-CBS-chiral oxazaborolidine and toluene solution thereof |
WO2010129509A1 (en) * | 2009-05-07 | 2010-11-11 | Eli Lilly And Company | Vinyl indazolyl compounds |
CN102971306A (en) * | 2010-05-14 | 2013-03-13 | 医疗技术研究局 | Pyrazolopyridines as inhibitors of the kinase LRRK2 |
CN103153983A (en) * | 2010-10-05 | 2013-06-12 | 伊莱利利公司 | Crystalline (r) - (e) -2- (4- (2- (5- (1- (3, 5 -dichloropyridin-4 -yl) ethoxy) - 1H - indazol - 3 - yl) vinyl) -1 H- pyrazol- 1 -yl) ethanol and its use as FGFR inhibitor |
Non-Patent Citations (1)
Title |
---|
ELIAS J.COREY等: "Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method", 《ANGEW. CHEM. INT. ED.》, vol. 37, 31 December 1998 (1998-12-31), pages 1987 - 2012 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111484393A (en) * | 2019-01-28 | 2020-08-04 | 上海茂晟康慧科技有限公司 | Preparation method of cis, cis-3, 5-dimethyl-1-cyclohexanol |
Also Published As
Publication number | Publication date |
---|---|
CN103819396B (en) | 2016-06-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103232336A (en) | Green synthesis method for substituted ketone | |
Wang et al. | Enantiopure N-ferrocenylmethylaziridin-2-ylmethanols from l-serine: Synthesis, crystal structure and applications | |
Le et al. | Synthesis of a new urea derivative: a dual-functional organocatalyst for Knoevenagel condensation in water | |
CN103044479A (en) | Synthetic method for bactericide of silthiopham | |
Chelucci et al. | Steric versus electronic effects of the ligand in the enantioselective palladium-catalyzed allylic alkylation with chiral oxazolinylpyridines | |
CN101146812B (en) | Optically active ammonium salt compound, production intermediate thereof and method for producing same | |
CN102952130B (en) | The method of chiral synthesize (S, S)-2,8-diazabicyclo nonane | |
Xing et al. | Chiral SO/P hybrid ligands: an enantioselective switch in palladium-catalyzed asymmetric allylic etherifications | |
CN105820113A (en) | Method for preparing Crizotinib chiral intermediate | |
CN104689849B (en) | One class phosphamide (primary) secondary amine bifunctional catalyst and its synthetic method | |
Sakurai et al. | Et-duphos-nickel-catalyzed asymmetric arylation of benzaldehyde derivatives bearing an ortho-Me2PhSi group with potassium aryltriolborates | |
CN103819396A (en) | Synthesis method of chiral 1-(3,5-dichloropyridine-4-yl)-ethanol | |
Shao et al. | Easily accessible chiral dicyclopentadiene ligands for rhodium-catalyzed enantioselective 1, 4-addition reactions | |
CN102320986B (en) | Preparation method for clopidogrel intermediate | |
CN103601706A (en) | Method for synthesizing natural product Jaspine B isomer | |
Ishibashi et al. | Azacalix [4] arene tetramethyl ether with inherent chirality generated by substitution on the nitrogen bridges | |
CN107513056B (en) | A kind of synthetic method of the quinolines of the group containing tetrahydrofuran | |
CN101967075A (en) | Method for synthesizing terminal alkyne compound by using 3-aryl-2,3-dibromopropionic acid | |
Knauer et al. | Palladium-catalysed C–C coupling reactions in the enantioselective synthesis of 2, 4-disubstituted 4, 5-dehydropiperidines using galactosylamine as a stereodifferentiating auxiliary | |
Sugimoto et al. | Enantioselective hydrogen atom transfer to α-sulfonyl radicals controlled by selective coordination of a chiral Lewis acid to an enantiotopic sulfonyl oxygen | |
CN109942553B (en) | Synthesis and conversion method of chiral 3,4, 6-trisubstituted tetrahydro 2H-pyran-2-one compound | |
Thorat et al. | An efficient route for the allylation of arylaldehydes to give enantiopure homoallylic alcohols | |
CN102822161A (en) | Method for producing optically active n-monoalkyl-3-hydroxy-3-arylpropylamine compound | |
Capracotta et al. | Chiral amino alcohols derived from (S)-6-chloronicotine as catalysts for asymmetric synthesis | |
CN101486696B (en) | Preparation of 2,5-dimethyl furan-3,4-dicarboxylic acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160615 Termination date: 20170226 |