CN103833560B - (S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol - Google Patents
(S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol Download PDFInfo
- Publication number
- CN103833560B CN103833560B CN201310097496.4A CN201310097496A CN103833560B CN 103833560 B CN103833560 B CN 103833560B CN 201310097496 A CN201310097496 A CN 201310097496A CN 103833560 B CN103833560 B CN 103833560B
- Authority
- CN
- China
- Prior art keywords
- preparation
- combination
- chloro
- acid
- cyclopropyl
- 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.)
- Active
Links
Abstract
<b>The present invention relates to</b><b>(S)-5-</b><b>Chlorine</b><b>-</b><b>α</b><b>-</b><b>Cyclopropyne base</b><b>-2-</b><b>Amino</b><b>-?</b><b>α</b><b>-</b><b>The preparation method of trifluoromethyl benzyl alcohol, comprises the steps:</b><b>-10</b><b>DEG C</b><b>~ 30</b><b>Under DEG C condition, (</b><b>1R, 2S</b><b>)</b><b>-1-</b><b>Phenyl</b><b>-2-</b><b>(</b><b>1-</b><b>Pyrrolidinyl)</b><b>-1-</b><b>Propyl alcohol,</b><b>Zn (II)</b><b>Under salt and highly basic existence condition,</b><b>4-</b><b>Chlorine</b><b>-2-</b><b>There is addition reaction in the slaine (structure is suc as formula shown in III) of trifluoroacetyl aniline and cyclopropyl acethlene, to obtain final product in solvent. The method does not need to use inflammable and explosive butyl lithium, without using dependence on import only, expensive, inflammable and explosive diethyl zinc, has reaction condition gentleness, raw material is cheap and easy to get yet, and product purity is higher, low (cost approximately for safety and environmental protection, cost</b><b>30%</b><b>), reaction dissolvent can realize circulation recycling, be easy to the advantages such as the large production of scale.</b><b/>
Description
Technical field
[0001] the invention belongs to field of medicine preparing technology, be specifically related to the preparation method of efavirenz intermediate (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol.
Background technology
[0002]The chemistry of efavirenz is by name: the chloro-4-cyclopropyl acethlene base-4-of (-)-6-Trifluoromethyl-1,4-dihydro-2H-3,1-Ben Bing dioxazine-2-ketone (structure is suc as formula shown in I), be the orally active non-nucleoside reverse transcriptase inhibitor of a class, HIV-1 virus is had to good inhibitory action.
(formula I)
Existing bibliographical information, the preparation key of efavirenz is to build chiral centre, makes intermediate (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol (structure is suc as formula shown in II).
(formula II)
Preparation method about (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol comprises: 1, document (WO9845278; WO9827073; preparation technology is as shown in Figure 1) preparation method of (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol disclosed; the method by chloro-4-2-trifluoroacetyl aniline after amido protecting; with cyclopropyl acethlene under chiral ligand and highly basic (as butyl lithium) exist; and carry out after addition reaction under low temperature (as-78 DEG C) condition; deaminate protecting group, to obtain final product. The method, in the time building chiral centre, need to use greatly excessive chiral ligand and highly basic, and reaction need be carried out under low temperature (below 60 DEG C) condition, and highly basic (butyl lithium) is inflammable explosive article, have severe reaction conditions, handling safety has much room for improvement, and is not easy to the defects such as industrialization. 2, document (Angew.Chem.Int.Ed, 2011,50(13), 2957-2961; 1999; 38(5); 711-713; preparation technology is as shown in Figure 2) preparation method of (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol disclosed; the method by chloro-4-2-trifluoroacetyl aniline under chiral ligand and highly basic exist; carry out addition reaction with the slaine of cyclopropyl acethlene, to obtain final product. The method is at room temperature reacted, and has shortened reactions steps, but needs to use expensive, only to rely on import diethyl zinc reagent, has the defects such as production cost is high, large-scale production is restricted.
Summary of the invention
The object of the present invention is to provide the preparation method of one (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol; comprise the steps: under-10 DEG C ~ 30 DEG C conditions; at (1R; 2S)-1-phenyl-2-(1-pyrrolidinyl) under-1-propyl alcohol, Zn (II) salt and highly basic existence condition; there is addition reaction in the slaine (structure is suc as formula shown in III) of the chloro-2-trifluoroacetyl aniline of 4-and cyclopropyl acethlene, to obtain final product in solvent.
(formula III)
In the preferred technical solution of the present invention, described Zn (II) salt is selected from any or its combination in TFMS zinc, zinc chloride, zinc bromide, zinc iodide.
In the preferred technical solution of the present invention, described highly basic be selected from sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, lithium hydride, sodium hydride, hydrofining, Sodamide, RMgX any or its combination, wherein, R is selected from C
1
-C
6
Any or its combination of alkyl, phenyl, substituted-phenyl, benzyl, X is selected from any or its combination of Cl, Br, I.
In the preferred technical solution of the present invention, described solvent is selected from any or its combination in oxolane, 2-methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene, benzene, n-hexane, normal heptane.
In the preferred technical solution of the present invention, the slaine of described cyclopropyl acethlene is reacted and makes at ambient temperature with highly basic by cyclopropyl acethlene, and wherein, the M in the slaine of cyclopropyl acethlene is selected from Li
+
、Na
+
、K
+
、(MgX)
+
Any or its combination, X be selected from Cl, Br, I any or its combination, the mol ratio of cyclopropyl acethlene and highly basic is 1 ~ 1.2:1, is preferably 1:1; Described highly basic be selected from lithium hydride, sodium hydride, hydrofining, Sodamide, RMgX any or its combination, R is selected from C
1
-C
6
Any or its combination of alkyl, phenyl, substituted-phenyl, benzyl, X is selected from any or its combination of Cl, Br, I.
In the preferred technical solution of the present invention, after addition reaction completely, in reactant liquor, add after acidic aqueous solution cancellation reaction, by the crude product making crystallization in solvent, to obtain final product.
In the preferred technical solution of the present invention, the acid of composition acidic aqueous solution is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, nitric acid, C
1
-C
6
Small molecular organic acid in any or its combination.
In the preferred technical solution of the present invention, the concentration of acidic aqueous solution is 0.5-5N, is preferably 1N.
In the preferred technical solution of the present invention, the consumption of acidic aqueous solution is 2 ~ 8 equivalents, is preferably 3 ~ 5 equivalents.
In the preferred technical solution of the present invention, described recrystallisation solvent is selected from any or its combination of water, methyl alcohol, ethanol, isopropyl alcohol, benzene, toluene, benzinum, n-hexane, normal heptane, oxolane, 2-methyltetrahydrofuran.
Another object of the present invention is to provide (S)-5-chloro-α-cyclopropyne base-2-preparation method of amino-α-trifluoromethyl benzyl alcohol, comprise the steps:
1) highly basic is suspended in solvent, makes highly basic suspension, wherein, described highly basic be selected from sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, lithium hydride, sodium hydride, hydrofining, Sodamide, RMgX any or its combination, R is selected from C
1
-C
6
Any or its combination of alkyl, phenyl, substituted-phenyl, benzyl, X is selected from any or its combination of Cl, Br, I, and described solvent is selected from any or its combination in oxolane, 2-methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene, benzene, n-hexane, normal heptane;
2) at ambient temperature, the highly basic hanging drop making in step 1) is added to (1R, 2S)-1-phenyl-2-(1-pyrrolidinyl) in the mixed solution of-1-propyl alcohol and trifluoroethanol, stir, add after Zn (II) salt, stir, make reaction mixture, wherein, described Zn (II) salt is selected from any or its combination in TFMS zinc, zinc chloride, zinc bromide, zinc iodide;
3) in step 2) slowly add the slaine of cyclopropyl acethlene in the reaction mixture that makes, be stirred to and react completely, wherein, the slaine of described cyclopropyl acethlene is reacted and makes at ambient temperature with highly basic by cyclopropyl acethlene, wherein, the M in the slaine of cyclopropyl acethlene is selected from Li
+
、Na
+
、K
+
、(MgX)
+
Any or its combination, X be selected from Cl, Br, I any or its combination, the mol ratio of cyclopropyl acethlene and highly basic is 1 ~ 1.2:1, is preferably 1:1;
4) reactant liquor is cooled to 5-10 DEG C; add after the chloro-2-trifluoroacetyl aniline of 4-; be warming up to again room temperature; to reacting completely; in reactant liquor, add after acidic aqueous solution cancellation reaction; by the crude product making crystallization in solvent, make (S)-5-chloro-α-cyclopropyne base-2-amido-α-trifluoromethyl benzyl alcohol.
In the preferred technical solution of the present invention, the acid of composition acidic aqueous solution is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, nitric acid, C
1
-C
6
Small molecular organic acid in any or its combination.
In the preferred technical solution of the present invention, the concentration of acidic aqueous solution is 0.5-5N, is preferably 1N.
In the preferred technical solution of the present invention, the consumption of acidic aqueous solution is 2 ~ 8 equivalents, is preferably 3 ~ 5 equivalents.
In the preferred technical solution of the present invention, described recrystallisation solvent is selected from any or its combination of water, methyl alcohol, ethanol, isopropyl alcohol, benzene, toluene, benzinum, n-hexane, normal heptane, oxolane, 2-methyltetrahydrofuran.
The present invention obtain hydrogen spectrum (
1
HNMR) instrument that data are used is 400 megahertz NMRs (BrukerAdvanceII400MHz) of Brooker company. Tetramethylsilane (TMS) is marked in doing, and room temperature is collected. Chemical shift (δ) is 1,000,000/(ppm). The unimodal s that is denoted as, doublet is denoted as d, and triplet is denoted as t, and quartet is denoted as q, and multiplet is denoted as m, the wide unimodal brs that is denoted as. Coupling constant is denoted as j, and unit is Hz. Deuterated solvent is deuterochloroform (CDCl
3
)。
It is Shimadzu LC-MS instrument (ShimadzuLCMS2010EV) that the present invention obtains the instrument that mass spectrum (MS) data use, and forward (positive) provides the quasi-molecular ions (MH of molecular weight hydrogenation
+
)。
Chirality high pressure liquid chromatography of the present invention (ChiralHPLC) post is ChiralpakAD-H, pillar is of a size of 0.46 centimetre x25 centimetre (0.46cm Ф x25cm), mobile phase n-hexane is 85 to 15 with the ratio of isopropyl alcohol, flow velocity is 1 milliliter per minute, detecting wavelength is 254 nanometers, and retention time is 6.89 minutes and 11.05 minutes.
Enantiomeric excess of the present invention (ee value) is denoted as: ee%.
Except as otherwise noted, while the present invention relates to the percentage between liquid and liquid, described percentage is volume/volume percentage; While the present invention relates to the percentage between liquid and solid, described percentage is volume/weight percentage; While the present invention relates to the percentage between solid and liquid, described percentage is weight/volume percent; All the other are weight/percentage by weight.
Compared with prior art, the present invention has following useful technique effect:
1, preparation method of the present invention does not need to use inflammable and explosive butyl lithium; and do not use dependence on import only, expensive, inflammable and explosive diethyl zinc; reaction condition gentleness; do not need ultralow temperature (78 ° of C); have raw material cheap and easy to get, product purity is higher, safety, environmental protection, cost low (cost approximately 30%), reaction dissolvent can realize circulation recycling, be easy to the advantages such as the large production of scale.
Brief description of the drawings
Preparation technology's flow process of disclosed (the S)-5-of Fig. 1 document chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol.
Preparation technology's flow process of disclosed (the S)-5-of Fig. 2 document chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol.
Preparation technology's flow process of Fig. 3 the present invention (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further described, but scope of the present invention is not limited to following embodiment.
Embodiment 1(S) preparation of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol
(S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol, comprises the steps:
1) under nitrogen protection, the tetrahydrofuran solution that is 1.6M benzylmagnesium chloride by 135ml concentration is placed in 1000ml four-hole bottle, be cooled to 5-10 DEG C, slowly drip 9g trifluoroethanol and 30g chiral ligand ((1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propyl alcohol) tetrahydrofuran solution;
2) drip and finish, at ambient temperature, stir after 1h, add 39g TFMS zinc, stir after 5h, then to add 75ml concentration be the tetrahydrofuran solution of ring the third acetenyl chlorination magnesium of 1.5M, stir after 1h, then add the chloro-2-trifluoroacetyl aniline of 4-20g, stirred overnight at room temperature;
3) TLC detects to after reacting completely, and adds after aqueous citric acid solution cancellation reaction, adopts toluene extractive reaction product, then toluene extract is concentrated into dry;
4) with toluene: the mixed solvent that the volume ratio of normal heptane is 4:1 is by toluene concentrate recrystallization, dry, makes (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol 21g, and solid is white in color.
Yield is that 81%, ee value is 99.5%.
δ(
1
HNMR,CDCl
3
)：7.52(d,1H,J=2.4Hz),7.12(dd,1H,J=2.4and8.7Hz),6.61(d,1H,J=8.7Hz),4.70(s,1H),4.39(s,2H),1.39(m,1H),0.85(m,1H)ppm。
+
。
Embodiment 2(S) preparation of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol
(S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol, comprises the steps:
1) under nitrogen protection, 8g sodium hydride and 135ml tetrahydrofuran solution are inserted in 1000ml four-hole bottle, stir, be cooled to 5-10 DEG C, slowly drip 9g trifluoroethanol and 30g chiral ligand ((1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propyl alcohol) tetrahydrofuran solution;
2) drip and finish, after stirring at room temperature 1h, add 39g TFMS zinc, stir 5h, then to add 75ml concentration be the tetrahydrofuran solution that 1.5M encircles the third acetenyl chlorination magnesium, stir after 1h, then add the chloro-2-trifluoroacetyl aniline of 4-20g, stirred overnight at room temperature;
3) TLC detects to after reacting completely, and adds after aqueous citric acid solution cancellation reaction, adopts toluene extractive reaction product, then toluene extract is concentrated into dry;
4) with toluene: the mixed solvent that the volume ratio of normal heptane is 4:1 is by toluene concentrate recrystallization, dry, makes (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol 22.3g, and solid is white in color.
Yield is that 86%, ee value is 99.2%.
δ(
1
HNMR,CDCl
3
)：7.52(d,1H,J=2.4Hz),7.12(dd,1H,J=2.4and8.7Hz),6.61(d,1H,J=8.7Hz),4.70(s,1H),4.39(s,2H),1.39(m,1H),0.85(m,1H)ppm。
+
。
Embodiment 3(S) preparation of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol
(S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol, comprises the steps:
1) under nitrogen protection, the tetrahydrofuran solution that is 1.6M benzylmagnesium chloride by 135ml concentration is placed in 1000ml four-hole bottle, be cooled to 5-10 DEG C, slowly drip 9g trifluoroethanol and 30g chiral ligand ((1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propyl alcohol) tetrahydrofuran solution;
2) drip and finish, at ambient temperature, stir after 1h, add 15g zinc chloride, stir after 5h, then to add 75ml concentration be the tetrahydrofuran solution that 1.5M encircles the third acetenyl chlorination magnesium, stir after 1h, then add the chloro-2-trifluoroacetyl aniline of 4-20g, stirred overnight at room temperature;
3) TLC detects to after reacting completely, and adds after aqueous citric acid solution cancellation reaction, adopts toluene extractive reaction product, then toluene extract is concentrated into dry;
4) with toluene: the mixed solvent that the volume ratio of normal heptane is 4:1 is by toluene concentrate recrystallization, dry, makes (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol 22g, and solid is white in color.
Yield is that 85%, ee value is 99.3%.
δ(
1
HNMR,CDCl
3
)：7.52(d,1H,J=2.4Hz),7.12(dd,1H,J=2.4and8.7Hz),6.61(d,1H,J=8.7Hz),4.70(s,1H),4.39(s,2H),1.39(m,1H),0.85(m,1H)ppm。
+
。
Embodiment 4(S) preparation of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol
(S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol, comprises the steps:
1) under nitrogen protection, 8.5g Sodamide and methyl tertiary butyl ether(MTBE) 150ml are placed in 1000ml four-hole bottle, be cooled to 5-10 DEG C, slowly drip 9g trifluoroethanol and 30g chiral ligand ((1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propyl alcohol) methyl tertbutyl ethereal solution;
2) drip and finish, at ambient temperature, stir after 1h, add 39g TFMS zinc, stir after 5h, then to add 75ml concentration be the tetrahydrofuran solution that 1.5M encircles the third acetenyl chlorination magnesium, stir after 1h, then add the chloro-2-trifluoroacetyl aniline of 4-20g, stirred overnight at room temperature;
3) TLC detects to after reacting completely, and adds after aqueous citric acid solution cancellation reaction, adopts toluene extractive reaction product, then toluene extract is concentrated into dry;
4) with toluene: the mixed solvent that the volume ratio of normal heptane is 4:1 is by toluene concentrate recrystallization, dry, makes (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol 21.5g, and solid is white in color.
Yield is that 83%, ee value is 99.0%.
δ(
1
HNMR,CDCl
3
)：7.52(d,1H,J=2.4Hz),7.12(dd,1H,J=2.4and8.7Hz),6.61(d,1H,J=8.7Hz),4.70(s,1H),4.39(s,2H),1.39(m,1H),0.85(m,1H)ppm。
MS:290(MH+)。
Claims (9)
1. a preparation method for (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol, under comprisingState step: under-10 DEG C～30 DEG C conditions, (1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propyl alcohol,Under Zn (II) salt and benzylmagnesium chloride existence condition, the gold of the chloro-2-trifluoroacetyl aniline of 4-and cyclopropyl acethleneBelong to salt addition reaction occurs in solvent, to obtain final product, described Zn (II) salt is selected from TFMS zinc.
2. preparation method according to claim 1, described solvent is selected from oxolane, 2-methyl tetrahydrochysene furanMutter, any or its combination in methyl tertiary butyl ether(MTBE), ether, toluene, benzene, n-hexane, normal heptane.
3. preparation method according to claim 1, the slaine of described cyclopropyl acethlene is by cyclopropyl secondAlkynes reacts and makes at ambient temperature with highly basic, wherein, and the metal ion choosing in the slaine of cyclopropyl acethleneFrom Li+、Na+、K+、(MgX)+Any or its combination, X be selected from Cl, Br, I any or itsCombination, the mol ratio of cyclopropyl acethlene and highly basic is 1～1.2:1; Described highly basic be selected from lithium hydride, sodium hydride,In hydrofining, Sodamide, RMgX any or its combination, R is selected from C1-C6Alkyl, phenyl, getFor any or its combination of phenyl, benzyl, X is selected from any or its combination of Cl, Br, I.
4. preparation method according to claim 1 after addition reaction completely, adds in reactant liquorAfter acidic aqueous solution cancellation reaction, by the crude product making crystallization in solvent, to obtain final product.
5. a preparation method for (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol, under comprisingState step:
1) benzylmagnesium chloride is suspended in solvent, makes suspension, described solvent is selected from oxolane, 2-Any in methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene, benzene, n-hexane, normal heptaneOr its combination;
2) at ambient temperature, by step 1) suspension that makes splashes into (IR, 2S)-1-phenyl-2-(1-pyrroleCough up alkyl) in the mixed solution of-1-propyl alcohol and trifluoroethanol, stir, add Zn (II) salt, stir, make anti-Answer mixed liquor, wherein, described Zn (II) salt is selected from TFMS zinc;
3) in step 2) slowly add the slaine of cyclopropyl acethlene in the reaction mixture that makes, be stirred to anti-Should be complete, wherein, the slaine of described cyclopropyl acethlene is by cyclopropyl acethlene and highly basic at ambient temperatureReaction makes, and wherein, the metal ion in the slaine of cyclopropyl acethlene is selected from Li+、Na+、K+、(MgX)+Any or its combination, X be selected from Cl, Br, I any or its combination, cyclopropyl acethleneWith the mol ratio of highly basic be 1～1.2:1;
4) reactant liquor is cooled to 5-10 DEG C, adds the chloro-2-trifluoroacetyl aniline of 4-, be warming up to room temperature, extremelyReact completely, in reactant liquor, add after acidic aqueous solution cancellation reaction, the crude product making is tied in solventCrystalline substance, makes (S)-5-chloro-α-cyclopropyne base-2-amido-α-trifluoromethyl benzyl alcohol.
6. according to the preparation method described in claim 4 or 5, the acid of composition acidic aqueous solution is selected from hydrochloric acid, hydrogenBromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, C1-C6Small molecular organic acid in any or its combination.
7. according to the preparation method described in claim 4 or 5, wherein, the acid of composition acidic aqueous solution is selected fromCitric acid or acetic acid.
8. according to the preparation method described in claim 4 or 5, wherein, the concentration of acidic aqueous solution is0.5-5 Ν, the consumption of acidic aqueous solution is 2～8 equivalents.
9. preparation method according to claim 5, described recrystallisation solvent be selected from water, methyl alcohol, ethanol,Isopropyl alcohol, benzene, toluene, benzinum, n-hexane, normal heptane, oxolane, 2-methyltetrahydrofuranAny or its combination.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310097496.4A CN103833560B (en) | 2013-03-25 | 2013-03-25 | (S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310097496.4A CN103833560B (en) | 2013-03-25 | 2013-03-25 | (S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103833560A CN103833560A (en) | 2014-06-04 |
| CN103833560B true CN103833560B (en) | 2016-05-25 |
Family
ID=50797501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310097496.4A Active CN103833560B (en) | 2013-03-25 | 2013-03-25 | (S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103833560B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105330554B (en) | 2015-02-15 | 2017-07-11 | 上海迪赛诺药业股份有限公司 | The synthetic method of chiral cylopropyl acetenyl tertiary alcohol compound |
| CN106932501A (en) * | 2015-12-31 | 2017-07-07 | 上海奥博生物医药技术有限公司 | According to the assay method of non-alcohol content in a kind of efavirenz |
| CN106946718A (en) * | 2017-04-27 | 2017-07-14 | 武汉工程大学 | A kind of method for synthesizing efavirenz intermediate |
| CN108947855B (en) * | 2018-08-10 | 2021-10-22 | 江苏沙星化工有限公司 | Synthesis method of efavirenz key intermediate |
| CN113880693B (en) * | 2021-11-12 | 2022-08-23 | 盐城迪赛诺制药有限公司 | Method for recovering trifluoroethanol in multi-component solvent |
| CN113968791A (en) * | 2021-11-18 | 2022-01-25 | 盐城迪赛诺制药有限公司 | Preparation method of efavirenz key intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251582A (en) * | 1997-04-07 | 2000-04-26 | 杜邦药品公司 | Asymmetric synthesis of benzoxazinones via new intermediates |
| CN1449865A (en) * | 2003-05-16 | 2003-10-22 | 中国科学院上海有机化学研究所 | Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone |
| WO2009095931A2 (en) * | 2008-01-31 | 2009-08-06 | Aptuit Laurus Pvt Ltd | An efficient process to induce enantioselectivity in procarbonyl compounds |
| CN101786959A (en) * | 2009-01-23 | 2010-07-28 | 上海迪赛诺医药发展有限公司 | Method for preparing chiral cylopropyl acetenyl tertiary alcohol compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9073817B2 (en) * | 2008-01-31 | 2015-07-07 | Laurus Labs Private Limited | Efficient process to induce enantioselectivity in procarbonyl compounds |
-
2013
- 2013-03-25 CN CN201310097496.4A patent/CN103833560B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251582A (en) * | 1997-04-07 | 2000-04-26 | 杜邦药品公司 | Asymmetric synthesis of benzoxazinones via new intermediates |
| CN1327976A (en) * | 1997-04-07 | 2001-12-26 | 杜邦药品公司 | Benzoxazinone compounds asymmetrically synthesized from new intermediate |
| CN1449865A (en) * | 2003-05-16 | 2003-10-22 | 中国科学院上海有机化学研究所 | Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone |
| WO2009095931A2 (en) * | 2008-01-31 | 2009-08-06 | Aptuit Laurus Pvt Ltd | An efficient process to induce enantioselectivity in procarbonyl compounds |
| CN101786959A (en) * | 2009-01-23 | 2010-07-28 | 上海迪赛诺医药发展有限公司 | Method for preparing chiral cylopropyl acetenyl tertiary alcohol compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103833560A (en) | 2014-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103833560B (en) | (S) preparation method of-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol | |
| CN104447445B (en) | A kind of preparation method synthesizing Apremilast intermediate | |
| CN103880596B (en) | A kind of preparation method of Nitric acid butoconazole intermediate of applicable suitability for industrialized production | |
| CN104876956B (en) | The technique of one pot process boron aminated compounds | |
| CN103739500B (en) | A kind of synthesis of cinacalcet hydrochloride and process for purification | |
| CN102964313B (en) | Synthetic method of febuxostat | |
| CN102241662A (en) | Synthetic method of thiophene-3-ethanol | |
| CN107663190A (en) | A kind of Ni Lapani and its intermediate preparation method and midbody compound | |
| CN105153149B (en) | A kind of selective kinase inhibitors Palbociclib preparation method | |
| CN104310487A (en) | Method for preparing anhydrous manganese chloride under anhydrous reaction conditions | |
| CN101863829B (en) | Synthesis method of 3-fluorine-4-aminopyridine | |
| CN105273006B (en) | The preparation method of the tri isopropyl biphenyl of 2 dicyclohexylphosphontetrafluoroborate 2,4,6 | |
| CN103787968B (en) | The preparation method of compound | |
| CN106187787A (en) | A kind of preparation method of 2 amino 4 chlorodiphenyl ethers | |
| CN106831863B (en) | Montelukast sodium intermediate and its preparation method and application | |
| CN102757390B (en) | Method for preparing 2-methoxy-4-diazanyl-5-fluoropyrimidine | |
| CN101580473B (en) | Method for preparing N-methyl paranitroaniline | |
| CN107815321A (en) | The preparation method of lateral o-difluoro-benzene class liquid-crystal compounds containing cyclohexyl | |
| CN104829588B (en) | A kind of Preparation Method And Their Intermediate of benzo [b] thiophene | |
| CN101391969B (en) | Method for preparing N-methyl-2-(2,4-dichlorophenoxy) acetamide | |
| CN106608896B (en) | A kind of synthetic method of pharmaceutical intermediate | |
| CN103058856A (en) | Method for preparing 4-(2,4,5-trifluorophenyl)-5-oxobutyric acid | |
| CN104447402B (en) | The preparation method of m-trifluoromethyl benzene acetonitrile | |
| CN108084077B (en) | Synthetic method of zafirlukast intermediate | |
| CN105503551A (en) | Method for preparing 2,3-dimethyl benzaldehyde |
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 | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 236626 zone B, Taihe Economic and Technological Development Zone, Fuyang City, Anhui Province Patentee after: Anhui Baker Pharmaceutical Co.,Ltd. Address before: 236626 zone B, Taihe Economic and Technological Development Zone, Fuyang City, Anhui Province Patentee before: ANHUI BIOCHEM UNITED PHARMACEUTICAL Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: (S) -5-chlorine- a- Cyclopropynyl-2-amino- a- Preparation of trifluoromethyl benzyl alcohol Effective date of registration: 20220621 Granted publication date: 20160525 Pledgee: China Construction Bank Taihe sub branch Pledgor: Anhui Baker Pharmaceutical Co.,Ltd. Registration number: Y2022340000012 |