CN102584609A - Preparation method for salmeterol - Google Patents
Preparation method for salmeterol Download PDFInfo
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- CN102584609A CN102584609A CN2011100020463A CN201110002046A CN102584609A CN 102584609 A CN102584609 A CN 102584609A CN 2011100020463 A CN2011100020463 A CN 2011100020463A CN 201110002046 A CN201110002046 A CN 201110002046A CN 102584609 A CN102584609 A CN 102584609A
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- salmeterol
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- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 0 *C(c(cc1)cc(CO)c1O)O Chemical compound *C(c(cc1)cc(CO)c1O)O 0.000 description 1
Abstract
The invention discloses a preparation method for salmeterol expressed by formula 3. The preparation method comprises the following steps: in a solvent, under the catalysis of palladium carbon, causing the compound 1, compound 2 and hydrogen to be subjected to reduction ammoniation reaction, thereby obtaining the salmeterol. The preparation method provided by the invention has the advantages of mild reaction conditions, simple post-processing, lower cost, higher yield and easiness in realization of industrialization.
Description
Technical field
The preparation method who relates to a kind of Salmeterol that the present invention is concrete.
Background technology
Prepare Salmeterol (GB1200886) with the method for reduction amination and mainly reported following method:
Compound 1 and 0.5g (2mmol) compound 2 of
0.5g (2.73mmol) join in the 5ml methyl alcohol under 23 ℃; Reaction 0.5h; Add 0.5g (13.2mmol) Peng Qinghuana and continue to stir 7h; Reaction solution adds behind the water with ethyl acetate extraction; Obtain the finished product Salmeterol 0.25g, productive rate 30.1% through column chromatography.But this method is owing to using problems such as column chromatography purification method and productive rate are lower, and difficulty is applied to industry's enlarging production.
Summary of the invention
Technical problem to be solved by this invention is to purify through column chromatography in order to overcome in the existing method for preparing Salmeterol with reductive ammonification needs, and productive rate is lower, is difficult to be applied to defectives such as suitability for industrialized production, and a kind of preparation method of Salmeterol is provided.Preparing method's reaction conditions of the present invention is gentle, and aftertreatment is simple, and cost is lower, and productive rate is higher, is easy to realize industriallization.
Therefore, the present invention relates to a kind of preparation method suc as formula the Salmeterol shown in 3, it comprises the following step: in the solvent, under the catalysis of palladium carbon, compound 1, compound 2 and hydrogen are carried out reduction amination, get final product;
Wherein, the condition of described reduction amination all can be the normal condition of this type of palladium carbon catalytic hydrogenation of this area, the preferred especially following condition of the present invention:
Described preferred solvents be in methyl alcohol, ethanol and the THF one or more, better is ethanol.The volume mass of solvent and compound 1 than preferable be 1～200ml/g.
What the mol ratio of described compound 1 and compound 2 was preferable is 0.8～1.5: 1, and better is 1.1: 1.
Described palladium carbon (Pd/C) preferable for the massfraction of Pd is 5%～20% palladium carbon, better is 10%.The consumption of palladium carbon is preferable is 0.05～0.5 times of quality of compound 1, and better is 0.1～0.2 times.
What the pressure of described hydrogen was preferable is 0.5～2.5Mpa hydrogen, and that better is 2.0Mpa.
What the temperature of described reaction was preferable is 10 ℃～45 ℃, and better is 25 ℃.The time of described reaction preferable with detection reaction fully till, be generally preferred 12 hours 4～24 hours.
After described reduction amination finishes, can purify the preferred especially following post-treating method of the present invention by the conventional post-treating method in this area:
(1) with reacting liquid filtering, concentrated filtrate washs with extraction commonly used liquid concentrator with organic solvent, filter;
(2) filtrating with step (1) gained is adjusted to acidity with mineral acid, and water extracts organic layer, and water layer merges, and water layer is adjusted to alkalescence with mineral alkali, extracts with organic solvent with extraction commonly used then, concentrates organic layer, gets oily matter;
(3) in step (2) gained oily matter, add non-polar solvent and carry out crystallization, separate out pure Salmeterol, get final product.
In the step (1), described extraction use organic solvent preferable be in ETHYLE ACETATE, methylene dichloride and the trichloromethane etc. one or more, ethyl acetate.
In the step (2), described mineral acid can be the mineral acid of adjustment of acidity commonly used, one or more that preferable is in hydrochloric acid, sulfuric acid and the nitric acid etc., and preferred hydrochloric acid, that the concentration of hydrochloric acid is preferable is 1～4mol/L, that better is 2mol/L.Described be adjusted to acid preferable be 2～3 for regulating pH.Described mineral alkali can be the mineral alkali of adjusting commonly used alkalescence, one or more that preferable be in sodium hydrogencarbonate, yellow soda ash, salt of wormwood and the saleratus, and preferred sodium hydrogencarbonate, better is saturated sodium bicarbonate.It is described that to be adjusted to alkalescence preferable be 8～9 for regulating pH.Described extraction use organic solvent preferable be in ETHYLE ACETATE, methylene dichloride and the trichloromethane etc. one or more, ethyl acetate.
In the step (3), described non-polar solvent can be the conventional non-polar solvent in this area, and like in normal hexane, sherwood oil and the ether solvent one or more, preferred ether solvent, better is MTBE.
Described post-treating method is better comprises the following step: with reacting liquid filtering, concentrated filtrate will be filtrated with the ETHYLE ACETATE washing, filter; Using the hydrochloric acid of 2mol/L to regulate pH filtrating is 2～3, with water extraction ethyl acetate layer, water layer is merged, and using saturated sodium bicarbonate solution to regulate water layer pH is 8～9; Use ethyl acetate extraction, concentrate ethyl acetate layer, get oily matter; Add MTBE, separate out pure Salmeterol, get final product.
Among the present invention, above-mentioned each preferred feature can promptly get each preferred embodiments of the present invention in arbitrary combination under the prerequisite of this area general knowledge.
Among the present invention, described room temperature is 18～25 ℃.
Except that specified otherwise, raw material that the present invention relates to and reagent are all commercially available to be got.
Positive progressive effect of the present invention is: preparing method's productive rate of the present invention is higher, and reaction conditions is gentle, and operating process and aftertreatment are easy, and be with low cost, is easy to realize suitability for industrialized production.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1
In autoclave, add the compound 1 and 0.5g (2mmol) compound 2 of 0.4g (2.2mmol) successively, the 0.05g massfraction is 10%Pd/C, 50ml absolute ethyl alcohol, and sealing feeds 2.0Mpa hydrogen, stirring at room 12h.Filter, filtrating concentrates, and with the washing of 50ml ETHYLE ACETATE, filters, and filtrating is regulated pH=2-3 with the hydrochloric acid of 2mol/L; Layering, with water extraction ethyl acetate layer, water layer merges, and regulates water layer pH=8-9, ethyl acetate extraction with saturated sodium bicarbonate solution; The combined ethyl acetate layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml MTBE and stirs, and separates out white solid Salmeterol 0.67g, productive rate 80.7%.The structure appraising datum of product is following:
M.p.75-76 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 98%
Embodiment 2
In autoclave, add the compound 1 and 0.5g (2mmol) compound 2 of 0.46g (2.5mmol) successively, the 0.1g massfraction is 20%Pd/C, 50ml absolute ethyl alcohol, and sealing feeds 2.0Mpa hydrogen, stirring at room 24h.Filter, filtrating concentrates, and with the washing of 50ml ETHYLE ACETATE, filters, and filtrating is regulated pH=2-3 with the hydrochloric acid of 2mol/L; Layering, with water extraction ethyl acetate layer, water layer merges, and regulates water layer pH=8-9, ethyl acetate extraction with saturated sodium bicarbonate solution; The combined ethyl acetate layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml MTBE and stirs, and separates out white solid Salmeterol 0.68g, productive rate 81.9%.The structure appraising datum of product is following:
M.p.76-77 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 97%
Embodiment 3
In autoclave, add the compound 1 and 0.82g (3.3mmol) compound 2 of 0.4g (2.2mmol) successively, the 0.04g massfraction is 10%Pd/C, 50ml absolute ethyl alcohol, and sealing feeds 2.0Mpa hydrogen, stirring at room 12h.Filter, filtrating concentrates, and with the washing of 50ml ETHYLE ACETATE, filters, and filtrating is regulated pH=2-3 with the hydrochloric acid of 2mol/L; Layering, with water extraction ethyl acetate layer, water layer merges, and regulates water layer pH=8-9, ethyl acetate extraction with saturated sodium bicarbonate solution; The combined ethyl acetate layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml MTBE and stirs, and separates out white solid Salmeterol 0.67g, productive rate 73.3%.The structure appraising datum of product is following:
M.p.75-76 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 97%
Embodiment 4
In autoclave, add the compound 1 and 0.5g (2mmol) compound 2 of 0.4g (2.2mmol) successively, the 0.05g massfraction is 10%Pd/C, 50ml absolute ethyl alcohol, and sealing feeds 20Mpa hydrogen, stirring at room 24h.Filter, filtrating concentrates, and with the washing of 50ml ETHYLE ACETATE, filters, and filtrating is regulated pH=2-3 with the hydrochloric acid of 2mol/L; Layering, with water extraction ethyl acetate layer, water layer merges, and regulates water layer pH=8-9, ethyl acetate extraction with saturated sodium bicarbonate solution; The combined ethyl acetate layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml MTBE and stirs, and separates out white solid Salmeterol 0.65g, productive rate 78.3%.The structure appraising datum of product is following:
M.p.75-76 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 97%
Embodiment 5
In autoclave, add the compound 1 and 0.5g (2mmol) compound 2 of 0.4g (2.2mmol) successively, the 0.05g massfraction is 10%Pd/C, 50ml anhydrous methanol, and sealing feeds 0.5Mpa hydrogen, and 10 ℃ are stirred 4h down.Filter, filtrating concentrates, and with the washing of 50ml ETHYLE ACETATE, filters, and filtrating is regulated pH=2-3 with the hydrochloric acid of 2mol/L; Layering, with water extraction ethyl acetate layer, water layer merges, and regulates water layer pH=8-9, ethyl acetate extraction with saturated sodium bicarbonate solution; The combined ethyl acetate layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml MTBE and stirs, and separates out white solid Salmeterol 0.38g, productive rate 45.8%.The structure appraising datum of product is following:
M.p.74-76 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 96%
Embodiment 6
In autoclave, add the compound 1 and 0.5g (2mmol) compound 2 of 0.4g (2.2mmol) successively, the 0.025g massfraction is 5%Pd/C, 50ml absolute ethyl alcohol, and sealing feeds 2.5Mpa hydrogen, and 45 ℃ are stirred 12h down.Filter, filtrating concentrates, and with the washing of 50ml ETHYLE ACETATE, filters, and filtrating is regulated pH=2-3 with the hydrochloric acid of 2mol/L; Layering, with water extraction ethyl acetate layer, water layer merges, and regulates water layer pH=8-9, ethyl acetate extraction with saturated sodium bicarbonate solution; The combined ethyl acetate layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml MTBE and stirs, and separates out white solid Salmeterol 0.51g, productive rate 61.4%.The structure appraising datum of product is following:
M.p.75-76 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 97%
Embodiment 7
In autoclave, add the compound 1 and 1.47mmol compound 2 of 0.4g (2.2mmol) successively, the 0.2g massfraction is 10%Pd/C, 20ml absolute ethyl alcohol, and sealing feeds 2.0Mpa hydrogen, stirring at room 12h.Filter, filtrating concentrates, and with the washing of 50ml ETHYLE ACETATE, filters, and filtrating is regulated pH=2-3 with the hydrochloric acid of 2mol/L; Layering, with water extraction ethyl acetate layer, water layer merges, and regulates water layer pH=8-9, ethyl acetate extraction with saturated sodium bicarbonate solution; The combined ethyl acetate layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml MTBE and stirs, and separates out the white solid Salmeterol, productive rate 80%.The structure appraising datum of product is following:
M.p.75-76 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 98%
Embodiment 8
In autoclave, add the compound 1 and 0.5g (2mmol) compound 2 of 0.4g (2.2mmol) successively, the 0.05g massfraction is 10%Pd/C, 80ml absolute ethyl alcohol, and sealing feeds 2.0Mpa hydrogen, stirring at room 12h.Filter, filtrating concentrates, and with the 50ml washed with dichloromethane, filters, and filtrating is regulated pH=2-3 with the sulfuric acid of 1mol/L; Layering, with water extraction dichloromethane layer, water layer merges, and regulates water layer pH=8-9, dichloromethane extraction with saturated sodium carbonate solution; The combined dichloromethane layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml normal hexane and stirs, and separates out the white solid Salmeterol, productive rate 80%.The structure appraising datum of product is following:
M.p.75-76 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 98%
Embodiment 9
In autoclave, add the compound 1 and 0.5g (2mmol) compound 2 of 0.4g (2.2mmol) successively, the 0.05g massfraction is 10%Pd/C, 0.4ml absolute ethyl alcohol, and sealing feeds 2.0Mpa hydrogen, stirring at room 12h.Filter, filtrating concentrates, and with the washing of 50ml trichloromethane, filters, and filtrating is regulated pH=2-3 with the nitric acid of 4mol/L; Layering, with water extraction trichloromethane layer, water layer merges, and regulates water layer pH=8-9, chloroform extraction with saturated potassium hydrogen carbonate solution; Merge the trichloromethane layer, washing, the saturated common salt water washing, anhydrous sodium sulfate drying filters; Filtrating concentrates to such an extent that get oily matter, adds the 10ml petroleum ether and stirring, separates out the white solid Salmeterol, productive rate 78%.The structure appraising datum of product is following:
M.p.75-76 ℃ (bibliographical information 75-77 ℃)
1HNMR(CDCl
3，400MHz)：1.1-1.6(m，12H)，2.5-2.8(m，6H)，3.3-3.5(m，4H)，4.5-4.6(m，1H)，4.7(s，2H)，4.9(br?s，4H)，6.7(d，1H)，6.9(s，1H)，7.00(d，1H)，7.1-7.3(m，5H)
MSI
+＝416(M
++H
+)，438(M
++H
++Na
+)
HPLC purity: 98%.
Claims (14)
1. the preparation method suc as formula the Salmeterol shown in 3 is characterized in that comprising the following step: in the solvent, under the catalysis of palladium carbon, compound 1, compound 2 and hydrogen are carried out reduction amination, get final product;
2. preparation method as claimed in claim 1 is characterized in that: described solvent is one or more in methyl alcohol, ethanol and the THF; Described solvent is 1～200ml/g with the volume mass ratio of compound 1.
3. preparation method as claimed in claim 1 is characterized in that: the mol ratio of described compound 1 and compound 2 is 0.8～1.5: 1.
4. preparation method as claimed in claim 1 is characterized in that: the massfraction that described palladium carbon is Pd is 5%～20% palladium carbon.
5. preparation method as claimed in claim 4 is characterized in that: the massfraction that described palladium carbon is Pd is 10% palladium carbon.
6. preparation method as claimed in claim 1 is characterized in that: the consumption of described palladium carbon is 0.05～0.5 times of quality of compound 1.
7. preparation method as claimed in claim 6 is characterized in that: the consumption of described palladium carbon is 0.1～0.2 times of molar weight of compound 1.
8. preparation method as claimed in claim 1 is characterized in that: the pressure of described hydrogen is 0.5～2.5Mpa.
9. preparation method as claimed in claim 8 is characterized in that: the pressure of described hydrogen is 2.0Mpa.
10. preparation method as claimed in claim 1 is characterized in that: the temperature of described reaction is 10 ℃～45 ℃; The time of described reaction with detection reaction fully till.
11. preparation method as claimed in claim 10 is characterized in that: the temperature of described reaction is 25 ℃.
12., it is characterized in that: after described reduction amination finishes, carry out following post-treating method like each described preparation method of claim 1～11:
(1) with reacting liquid filtering, concentrated filtrate washs with extraction commonly used liquid concentrator with organic solvent, filter;
(2) filtrating with step (1) gained is adjusted to acidity with mineral acid, layering, and water extracts organic layer, and water layer merges, and water layer is adjusted to alkalescence with mineral alkali, extracts with organic solvent with extraction commonly used then, concentrates organic layer, gets oily matter;
(3) in step (2) gained oily matter, add non-polar solvent and carry out crystallization, separate out pure Salmeterol, get final product.
13. preparation method as claimed in claim 12 is characterized in that:
In the step (1), described extraction uses organic solvent to be in ETHYLE ACETATE, methylene dichloride and the trichloromethane one or more;
And/or in the step (2), described mineral acid is one or more in hydrochloric acid, sulfuric acid and the nitric acid, and the concentration of hydrochloric acid is 1～4mol/L; The described acidity that is adjusted to is 2～3 for regulating pH; Described mineral alkali is one or more in sodium hydrogencarbonate, yellow soda ash, salt of wormwood and the saleratus; The described alkalescence that is adjusted to is 8～9 for regulating pH; Described extraction uses organic solvent to be in ETHYLE ACETATE, methylene dichloride and the trichloromethane one or more;
And/or in the step (3), described non-polar solvent is one or more in normal hexane, sherwood oil and the ether solvent.
14. preparation method as claimed in claim 13 is characterized in that: in the step (2), the concentration of described hydrochloric acid is 2mol/L; Described sodium hydrogencarbonate is a saturated sodium bicarbonate;
In the step (3), described ether solvent is a MTBE.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110002046.3A CN102584609B (en) | 2011-01-06 | 2011-01-06 | Preparation method for salmeterol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110002046.3A CN102584609B (en) | 2011-01-06 | 2011-01-06 | Preparation method for salmeterol |
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| CN102584609B CN102584609B (en) | 2015-05-27 |
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|---|---|---|---|
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1200886A (en) * | 1966-09-23 | 1970-08-05 | Allen & Hanburys Ltd | Phenylaminoethanol derivatives |
| EP0023385A1 (en) * | 1979-06-16 | 1981-02-04 | Beecham Group Plc | Ethanamine derivatives, their preparation and use in pharmaceutical compositions |
| CN101712622A (en) * | 2009-11-10 | 2010-05-26 | 浙江万里学院 | Method for preparing anti-asthmatic medicament of salmeterol |
-
2011
- 2011-01-06 CN CN201110002046.3A patent/CN102584609B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1200886A (en) * | 1966-09-23 | 1970-08-05 | Allen & Hanburys Ltd | Phenylaminoethanol derivatives |
| EP0023385A1 (en) * | 1979-06-16 | 1981-02-04 | Beecham Group Plc | Ethanamine derivatives, their preparation and use in pharmaceutical compositions |
| CN101712622A (en) * | 2009-11-10 | 2010-05-26 | 浙江万里学院 | Method for preparing anti-asthmatic medicament of salmeterol |
Non-Patent Citations (3)
| Title |
|---|
| 《ORGANIC LETTERS》 20021009 Robert N.Bream等 Synthesis of the beta2 Agonist (R)-Salmeterol Using a Sequence of Supported Reagents and Scavenging Agents 第3793-3796页 1-14 第4卷, 第22期 * |
| ROBERT N.BREAM等: "Synthesis of the β2 Agonist (R)-Salmeterol Using a Sequence of Supported Reagents and Scavenging Agents", 《ORGANIC LETTERS》, vol. 4, no. 22, 9 October 2002 (2002-10-09), pages 3793 - 3796, XP002273155, DOI: doi:10.1021/ol020128g * |
| 周玓等: "沙美特罗的一条新合成路线", 《中国药物化学杂志》, vol. 19, no. 2, 30 April 2009 (2009-04-30) * |
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| CN102584609B (en) | 2015-05-27 |
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