CN103833560A - Preparation method of (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol - Google Patents
Preparation method of (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol Download PDFInfo
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- CN103833560A CN103833560A CN201310097496.4A CN201310097496A CN103833560A CN 103833560 A CN103833560 A CN 103833560A CN 201310097496 A CN201310097496 A CN 201310097496A CN 103833560 A CN103833560 A CN 103833560A
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Abstract
The invention relates to a preparation method of (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol, which comprises the following steps that 4-chloro-2-trifluoroacetyl aniline and the metal salt (with a structure shown by the formula III) of cyclopropyl acetylene generate an addition reaction in a solvent in the presence of (1R, 2S)-1-phenyl-2-(1-pyrrolidyl)-1-propyl alcohol, Zn(II) salt and strong alkali at -10 to 30 DEG C to obtain (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol. Without using flammable and explosive butyl lithium or expensive and flammable and explosive diethyl zinc only depending on import, the method has the advantages of mild reaction conditions, cheap and easily-available raw materials, higher product purity, safety and environmental friendliness, low cost (the cost is reduced by about 30%), recycling of the reaction solvent, easiness in large-scale mass production and the like.
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 restraining effect.
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).
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 butyllithium) exist; and carry out after addition reaction under low temperature (as-78 DEG C) condition; deaminize 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 (butyllithium) is inflammable explosive article, have severe reaction conditions, operational 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 metal-salt 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 zinc ethyl 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-pyrrolidyl) under-1-propyl alcohol, Zn (II) salt and highly basic existence condition; there is addition reaction in the metal-salt (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.
in the preferred technical solution of the present invention, described Zn (II) salt is selected from any or its combination in trifluoromethanesulfonic acid zinc, zinc chloride, zinc bromide, zinc iodide.
in the preferred technical solution of the present invention, described highly basic be selected from sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, lithium hydride, sodium hydride, potassium hydride KH, sodium amide, RMg X 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 tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene, benzene, normal hexane, normal heptane.
in the preferred technical solution of the present invention, the metal-salt of described cyclopropyl acethlene is reacted and makes at ambient temperature with highly basic by cyclopropyl acethlene, and wherein, the M in the metal-salt 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, potassium hydride KH, sodium amide, 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 reaction solution, 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, Hydrogen bromide, hydroiodic acid HI, 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, Virahol, benzene, toluene, sherwood oil, normal hexane, normal heptane, tetrahydrofuran (THF), 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 methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, lithium hydride, sodium hydride, potassium hydride KH, sodium amide, RMg X 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 tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene, benzene, normal 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-pyrrolidyl) in the mixing solutions 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 trifluoromethanesulfonic acid zinc, zinc chloride, zinc bromide, zinc iodide;
3) in step 2) slowly add the metal-salt of cyclopropyl acethlene in the reaction mixture that makes, be stirred to and react completely, wherein, the metal-salt of described cyclopropyl acethlene is reacted and makes at ambient temperature with highly basic by cyclopropyl acethlene, wherein, the M in the metal-salt 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) reaction solution 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 reaction solution, 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, Hydrogen bromide, hydroiodic acid HI, 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, Virahol, benzene, toluene, sherwood oil, normal hexane, normal heptane, tetrahydrofuran (THF), 2-methyltetrahydrofuran.
the present invention obtain hydrogen spectrum (
1
hNMR) instrument that data are used is the 400 megahertz nuclear magnetic resonance analyser (Bruker Advance II 400 MHz) 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 br s 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 (Shimadzu LCMS 2010EV) 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 (Chiral HPLC) post is Chiralpak AD-H, pillar is of a size of 0.46 centimetre x25 centimetre (0.46cm Ф x25cm), moving phase normal hexane is 85 to 15 with the ratio of Virahol, flow velocity is 1 milliliter of 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 per-cent between liquid and liquid, described per-cent is volume/volume per-cent; While the present invention relates to the per-cent between liquid and solid, described per-cent is volume/weight per-cent; While the present invention relates to the per-cent between solid and liquid, described per-cent is weight/volume percent; All the other are weight/weight percent.
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 butyllithium; and do not use dependence on import only, expensive, inflammable and explosive zinc ethyl; reaction conditions gentleness; do not need very low 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 solvent can realize circulation recycling, be easy to the advantages such as the large production of mass-producing.
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.
?
Embodiment
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-pyrrolidyl)-1-propyl alcohol) tetrahydrofuran solution;
2) drip and finish, at ambient temperature, stir after 1h, add 39g trifluoromethanesulfonic acid zinc, stir after 5h, then to add 75ml concentration be the tetrahydrofuran solution of ring the third ethynyl 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 extraction liquid is concentrated into dry;
4) with toluene: the mixed solvent that the volume ratio of normal heptane is 4:1 is by toluene enriched material 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?=?2.4?and?8.7Hz),?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-pyrrolidyl)-1-propyl alcohol) tetrahydrofuran solution;
2) drip and finish, after stirring at room temperature 1h, add 39g trifluoromethanesulfonic acid zinc, stir 5h, then to add 75ml concentration be the tetrahydrofuran solution that 1.5M encircles the third ethynyl 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 extraction liquid is concentrated into dry;
4) with toluene: the mixed solvent that the volume ratio of normal heptane is 4:1 is by toluene enriched material 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?=?2.4?and?8.7Hz),?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-pyrrolidyl)-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 ethynyl 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 extraction liquid is concentrated into dry;
4) with toluene: the mixed solvent that the volume ratio of normal heptane is 4:1 is by toluene enriched material 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?=?2.4?and?8.7Hz),?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 sodium amide and methyl tertiary butyl ether 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-pyrrolidyl)-1-propyl alcohol) methyl tertbutyl ethereal solution;
2) drip and finish, at ambient temperature, stir after 1h, add 39g trifluoromethanesulfonic acid zinc, stir after 5h, then to add 75ml concentration be the tetrahydrofuran solution that 1.5M encircles the third ethynyl 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 extraction liquid is concentrated into dry;
4) with toluene: the mixed solvent that the volume ratio of normal heptane is 4:1 is by toluene enriched material 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?=?2.4?and?8.7Hz),?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 (10)
1. the preparation method of (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-pyrrolidyl) under-1-propyl alcohol, Zn (II) salt and highly basic existence condition; there is addition reaction in the metal-salt of the chloro-2-trifluoroacetyl aniline of 4-and cyclopropyl acethlene, to obtain final product in solvent.
2. preparation method according to claim 1, described Zn (II) salt is selected from any or its combination in trifluoromethanesulfonic acid zinc, zinc chloride, zinc bromide, zinc iodide.
3. preparation method according to claim 1 and 2, described highly basic be selected from sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, lithium hydride, sodium hydride, potassium hydride KH, sodium amide, RMg X any or its combination, wherein, R is selected from C
1-C
6any or its combination of alkyl, phenyl, substituted-phenyl, benzyl, X is selected from any or its combination of Cl, Br, I.
4. according to the preparation method described in claim 1-3 any one, described solvent is selected from any or its combination in tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene, benzene, normal hexane, normal heptane.
5. according to the preparation method described in claim 1-4 any one, the metal-salt of described cyclopropyl acethlene is reacted and makes at ambient temperature with highly basic by cyclopropyl acethlene, and wherein, the M in the metal-salt 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, potassium hydride KH, sodium amide, RMgX any or its combination, R is selected from C
1-C
6any or its combination of alkyl, phenyl, substituted-phenyl, benzyl, X is selected from any or its combination of Cl, Br, I.
6. according to the preparation method described in claim 1-5 any one, after addition reaction completely, in reaction solution, add after acidic aqueous solution cancellation reaction, by the crude product making crystallization in solvent, to obtain final product.
7. a preparation method for (S)-5-chloro-α-cyclopropyne base-2-amino-α-trifluoromethyl benzyl alcohol, comprises the steps:
1) highly basic is suspended in solvent, makes highly basic suspension, wherein, described highly basic be selected from sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, lithium hydride, sodium hydride, potassium hydride KH, sodium amide, RMg X any or its combination, R is selected from C
1-C
6any 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 tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether, ether, toluene, benzene, normal hexane, normal heptane;
2) at ambient temperature, the highly basic suspension making in step 1) splashes into (1R, 2S)-1-phenyl-2-(1-pyrrolidyl) in the mixing solutions of-1-propyl alcohol and trifluoroethanol, stir, add Zn (II) salt, stir, make reaction mixture, wherein, described Zn (II) salt is selected from any or its combination in trifluoromethanesulfonic acid zinc, zinc chloride, zinc bromide, zinc iodide;
3) in step 2) slowly add the metal-salt of cyclopropyl acethlene in the reaction mixture that makes, be stirred to and react completely, wherein, the metal-salt of described cyclopropyl acethlene is reacted and makes at ambient temperature with highly basic by cyclopropyl acethlene, wherein, the M in the metal-salt 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) reaction solution is cooled to 5-10 DEG C; add the chloro-2-trifluoroacetyl aniline of 4-; be warming up to room temperature; to reacting completely; in reaction solution, 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.
8. according to the preparation method described in claim 1-7 any one, the acid of composition acidic aqueous solution is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid, citric acid, acetic acid, C
1-C
6small molecular organic acid in any or its combination.
9. according to the preparation method described in claim 1-8 any one, the concentration of acidic aqueous solution is 0.5-5N, is preferably 1N, and more preferably the consumption of acidic aqueous solution is 2 ~ 8 equivalents, and also the consumption of the preferred acidic aqueous solution is 3 ~ 5 equivalents.
10. according to the preparation method described in claim 1-9 any one, described recrystallisation solvent is selected from any or its combination of water, methyl alcohol, ethanol, Virahol, benzene, toluene, sherwood oil, normal hexane, normal heptane, tetrahydrofuran (THF), 2-methyltetrahydrofuran.
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| WO2016127661A1 (en) * | 2015-02-15 | 2016-08-18 | 上海迪赛诺药业有限公司 | Synthesis process for chiral cyclopropyl ethynyl 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 |
| CN108947855A (en) * | 2018-08-10 | 2018-12-07 | 江苏沙星化工有限公司 | A kind of synthetic method of efavirenz key intermediate |
| CN113880693A (en) * | 2021-11-12 | 2022-01-04 | 盐城迪赛诺制药有限公司 | Method for recovering trifluoroethanol in multi-component solvent |
| CN115197075A (en) * | 2021-11-18 | 2022-10-18 | 盐城迪赛诺制药有限公司 | Preparation method of efavirenz key intermediate |
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| CN106946718A (en) * | 2017-04-27 | 2017-07-14 | 武汉工程大学 | A kind of method for synthesizing efavirenz intermediate |
| CN108947855A (en) * | 2018-08-10 | 2018-12-07 | 江苏沙星化工有限公司 | A kind of synthetic method of efavirenz key intermediate |
| CN113880693A (en) * | 2021-11-12 | 2022-01-04 | 盐城迪赛诺制药有限公司 | Method for recovering trifluoroethanol in multi-component solvent |
| 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 |
| CN115197075A (en) * | 2021-11-18 | 2022-10-18 | 盐城迪赛诺制药有限公司 | Preparation method of efavirenz key intermediate |
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