PL228397B1 - Method for producing R-(-)-2-bromo-1-(2'-methoxyphenylo)-ethan-1-ol - Google Patents
Method for producing R-(-)-2-bromo-1-(2'-methoxyphenylo)-ethan-1-olInfo
- Publication number
- PL228397B1 PL228397B1 PL407988A PL40798814A PL228397B1 PL 228397 B1 PL228397 B1 PL 228397B1 PL 407988 A PL407988 A PL 407988A PL 40798814 A PL40798814 A PL 40798814A PL 228397 B1 PL228397 B1 PL 228397B1
- Authority
- PL
- Poland
- Prior art keywords
- bromo
- ethan
- methoxyphenyl
- formula
- methoxyphenylo
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 238000000034 method Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 4
- 241000223254 Rhodotorula mucilaginosa Species 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- YRNDGUSDBCARGC-UHFFFAOYSA-N 2-methoxyacetophenone Chemical compound COCC(=O)C1=CC=CC=C1 YRNDGUSDBCARGC-UHFFFAOYSA-N 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- FROJNSZKFGHHNR-QMMMGPOBSA-N (1r)-2-bromo-1-(2-methoxyphenyl)ethanol Chemical compound COC1=CC=CC=C1[C@@H](O)CBr FROJNSZKFGHHNR-QMMMGPOBSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- GKNCPTLOPRDYMH-UHFFFAOYSA-N 2-bromo-1-(2-methoxyphenyl)ethanone Chemical compound COC1=CC=CC=C1C(=O)CBr GKNCPTLOPRDYMH-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- NICURWGAEFHESQ-UHFFFAOYSA-N (+)-(S)-tembamide Natural products C1=CC(OC)=CC=C1C(O)CNC(=O)C1=CC=CC=C1 NICURWGAEFHESQ-UHFFFAOYSA-N 0.000 description 1
- LBSKQOSGSUKVDG-QMMMGPOBSA-N (1r)-2-chloro-1-(3-chlorophenyl)ethanol Chemical compound ClC[C@H](O)C1=CC=CC(Cl)=C1 LBSKQOSGSUKVDG-QMMMGPOBSA-N 0.000 description 1
- DKYPDMHYDHHGRL-HTQZYQBOSA-N (4r,5r)-2-(3-nitrophenyl)-1,3,2-dioxaborolane-4,5-dicarboxylic acid Chemical compound O1[C@@H](C(O)=O)[C@H](C(=O)O)OB1C1=CC=CC([N+]([O-])=O)=C1 DKYPDMHYDHHGRL-HTQZYQBOSA-N 0.000 description 1
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- -1 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol Chemical compound 0.000 description 1
- XQJAHBHCLXUGEP-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(=O)CBr)C=C1 XQJAHBHCLXUGEP-UHFFFAOYSA-N 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- AWMVMTVKBNGEAK-UHFFFAOYSA-N Styrene oxide Chemical class C1OC1C1=CC=CC=C1 AWMVMTVKBNGEAK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 229950007304 denopamine Drugs 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229950008204 levosalbutamol Drugs 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000013048 microbiological method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- NICURWGAEFHESQ-HNNXBMFYSA-N n-[(2r)-2-hydroxy-2-(4-methoxyphenyl)ethyl]benzamide Chemical compound C1=CC(OC)=CC=C1[C@@H](O)CNC(=O)C1=CC=CC=C1 NICURWGAEFHESQ-HNNXBMFYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 102220201851 rs143406017 Human genes 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
(21) Numer zgłoszenia: 407988(21) Application number: 407988
Urząd Patentowy Rzeczypospolitej Polskiej (22) Data zgłoszenia: 24.04.2014 (51) Int CI.Patent Office of the Republic of Poland (22) Date of filing: April 24, 2014 (51) Int CI.
C12P 7/22 (2006.01) C12P 41/00 (2006.01) C12N 1/14 (2006.01) C12R 1/645 (2006.01) (54) Sposób wytwarzania R-(-)-2-bromo-1 -(2'-metoksyfenylo)-etan-1 -oluC12P 7/22 (2006.01) C12P 41/00 (2006.01) C12N 1/14 (2006.01) C12R 1/645 (2006.01) (54) Production method R - (-) - 2-bromo-1 - (2'-methoxyphenyl ) -ethane-1-ol
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PL 228 397 B1PL 228 397 B1
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest sposób wytwarzania R-(-)-2-bromo-1-(2'-metoksyfenylo)-etan-1-olu.The present invention relates to a process for the preparation of R - (-) - 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol.
Wynalazek ten może znaleźć zastosowanie w przemyśle farmaceutycznym do wytwarzania dogodnego bloku budulcowego w syntezie leków aryloetanoloaminowych, takich jak (R)-denopamina, (R)-salbutamol czy (R)-tembamid o aktywności hipoglikemicznej (Hamada H, Miura T, Kumobayashi H, Matsuda T, Harada T, Nakamura K; 2001. Asymmetric synthesis of (R)-2-chloro-1-(m-chlorophenyl)ethanol using acetone powder of Grotrichum candidum, Biotechnology Lett. 23, 1603-1606).This invention may find application in the pharmaceutical industry for the production of a convenient building block in the synthesis of arylethanolamine drugs, such as (R) -denopamine, (R) -salbutamol or (R) -tembamide with hypoglycemic activity (Hamada H, Miura T, Kumobayashi H, Matsuda T, Harada T, Nakamura K; 2001. Asymmetric synthesis of (R) -2-chloro-1- (m-chlorophenyl) ethanol using acetone powder of Grotrichum candidum, Biotechnology Lett. 23, 1603-1606).
Agoniści receptora 32-adrenergicznego działają za pośrednictwem swoistego receptora błonowego, umożliwiając uzyskanie rozkurczu mięśni gładkich oskrzeli. Receptor 32-adrenergiczny jest łańcuchem białkowym, który składa się z 413 aminokwasów kodowanych przez gen umiejscowiony w regionie 5 chromosomu (Johnson M. 2006. Molecular mechanisms of 32-adrenergic receptor function, response, and regulation. Journal of Allergy and Clinical Immunology: 117, 1, 18-24).32-adrenoceptor agonists act through a specific membrane receptor to relax the bronchial smooth muscle. The 32-adrenergic receptor is a protein chain that consists of 413 amino acids encoded by a gene located in the 5 region of chromosome (Johnson M. 2006. Molecular mechanisms of 32-adrenergic receptor function, response, and regulation. Journal of Allergy and Clinical Immunology: 117 , 1, 18-24).
Farmakologiczny efekt współcześnie dostępnych agonistów receptora 32-adrenergicznego o przedłużonym czasie działania jest zbliżony i sprowadza się zasadniczo do relaksacji mięśni gładkich, co prowadzi do rozszerzenia światła oskrzeli (Anderson G.P., Linden A., Rabe K.F. 1994. Why are long-acting beta-adrenoceptor agonists long-acting? European Respiratory Journal: 7, 569-578; Barnes P.J. 2001. Current therapy for asthma. New drugs for asthma, allergy and COPD. Karger Publishers, Basel).The pharmacological effect of the currently available 32-adrenergic receptor agonists with a prolonged duration of action is similar and is essentially the relaxation of smooth muscles, which leads to dilation of the bronchial lumen (Anderson GP, Linden A., Rabe KF 1994. Why are long-acting beta-adrenoceptor) agonists long-acting (European Respiratory Journal: 7, 569-578; Barnes PJ 2001. Current therapy for asthma. New drugs for asthma, allergy and COPD. Karger Publishers, Basel).
Znany jest proces otrzymywania racemicznego 2-bromo-1-(2'-metoksyfenylo)-etan-1-olu w wyniku redukcji 2-bromo-2'-metoksyacetofenonu wodno-dioksanowym roztworem NaBH4 (Perrone R., Berardi F., Leopoldo M., Tortorella V. Oxygen isosteric derivatives of 3-(3-hydroxyphenyl)W-n-propylpiperidine. J. Med. Chem. 1992, 35, 3045-3049).There is a known process for the preparation of racemic 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol by reduction of 2-bromo-2'-methoxyacetophenone with a water-dioxane solution of NaBH4 (Perrone R., Berardi F., Leopoldo M ., Tortorella V. Oxygen isosteric derivatives of 3- (3-hydroxyphenyl) Wn-propylpiperidine. J. Med. Chem. 1992, 35, 3045-3049).
Znana jest metoda enancjoselektywnej redukcji 2-bromo-4'-metoksyacetofenonu borowodorkiem litu modyfikowanym chiralnym związkiem boru, w wyniku tego procesu uzyskano S-(+)-2-bromo-1-(2'-metoksyfenylo)-etan-1-olu z konwersją 99% i nadmiarem enancjomerycznym 86% (Cordes D.B., Kwong T.J., Morgan K.A., Singaram B. Chiral styrene oxides from α-haloacetophenones using NaBH4 and TarB-NO2, a chiral Lewis acid. Tetrahedron Lett. 2006, 47, 349-351). W dostępnej literaturze nie znaleziono metody mikrobiologicznej uzyskiwania R-(-)-2-bromo-1-(2'-metoksyfenylo)-etan-1-olu.There is a known method of enantioselective reduction of 2-bromo-4'-methoxyacetophenone with lithium borohydride modified with chiral boron compound, as a result of this process S - (+) - 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol from 99% conversion and 86% ee (Cordes DB, Kwong TJ, Morgan KA, Singaram B. Chiral styrene oxides from α-haloacetophenones using NaBH4 and TarB-NO2, a chiral Lewis acid. Tetrahedron Lett. 2006, 47, 349-351 ). No microbiological method for obtaining R - (-) - 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol was found in the available literature.
Istota wynalazku polega na tym, że redukcję grupy karbonylowej substratu, którym jest 2-bromo-2'-metoksyacetofenon, do R-(-)-2-bromo-1-(2'-metoksyfenylo)-etan-1-olu, prowadzi się przy zastosowaniu wodnej kultury szczepu Rhodotorula rubra KCh 82, przy ciągłym mieszaniu reagentów. Produkt ekstrahuje się rozpuszczalnikiem organicznym nie mieszającym się z wodą i oczyszcza chromatograficznie. Otrzymuje się R-(-)-2-bromo-1-(2'-metoksyfenylo)-etan-1-ol z wydajnością 88% (konwersja według GC >99%).The essence of the invention is that the reduction of the carbonyl group of the substrate, which is 2-bromo-2'-methoxyacetophenone, to R - (-) - 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol is carried out by is carried out using an aqueous culture of the strain Rhodotorula rubra KCh 82 with constant mixing of the reagents. The product is extracted with a water-immiscible organic solvent and purified by chromatography. R - (-) - 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol is obtained in a yield of 88% (GC conversion> 99%).
Korzystne jest, gdy proces prowadzi się w temperaturze od 20 do 35°C.It is advantageous if the temperature is between 20 and 35 ° C.
Korzystnie również jest, gdy rozpuszczalnikiem organicznym jest chloroform.It is also preferred that the organic solvent is chloroform.
Zasadniczą zaletą wynalazku jest otrzymanie R-(-)-2-bromo-1-(2'-metoksyfenylo)-etan-1-ol z nadmiarem enancjomerycznym równym 98% jako jedynego produktu reakcji, z wydajnością 88% (konwersja według GC >99%), w temperaturze pokojowej i pH naturalnym dla szczepu.The main advantage of the invention is the preparation of R - (-) - 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol with an enantiomeric excess of 98% as the only reaction product, with a yield of 88% (GC conversion> 99 %), at room temperature and pH natural for the strain.
P r z y k ł a dP r z k ł a d
Do kolby Erlenmajera o pojemności 2000 cm3, w której znajduje się 500 cm3 sterylnej pożywki zawierającej 5 g aminobaku i 15 g glukozy, wprowadza się szczep Rhodotorula rubra KCh 82. Po 48 godzinach jego wzrostu dodaje się 100 mg 2-bromo-2'-metoksyacetofenon, o wzorze 1, rozpuszczonego w 1 cm3 acetonu. Transformację prowadzi się w 25 stopniach Celsjusza przy ciągłym wstrząsaniu przez 24 godziny. Następnie mieszaninę poreakcyjną ekstrahuje się trzykrotnie chloroformem, osusza bezwodnym siarczanem magnezu, po czym odparowuje się rozpuszczalnik. Otrzymany ekstrakt oczyszcza się chromatograficznie, używając jako eluentu mieszaniny acetonu i heksanu w stosunku 3:1.To the Erlenmeyer flask with a capacity of 2,000 cm 3, which is 500 cm 3 of a sterile medium containing 5 g aminobaku and 15 g of glucose, introduced strain Rhodotorula rubra SDS 82. After 48 hours, the growth was added 100 mg of 2-bromo-2 ' -metoksyacetofenon of formula 1, dissolved in 1 cm 3 of acetone. The transformation is carried out at 25 degrees Celsius with continuous shaking for 24 hours. The reaction mixture was then extracted three times with chloroform, dried with anhydrous magnesium sulfate, and then the solvent was evaporated. The extract obtained is purified by chromatography using a 3: 1 mixture of acetone and hexane as eluent.
Na tej drodze otrzymuje się 88 mg R-(-)-2-bromo-1-(2'-metoksyfenylo)-etan-1-ol (wydajność 88%).In this way, 88 mg of R - (-) - 2-bromo-1- (2'-methoxyphenyl) -ethan-1-ol are obtained (88% yield).
Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi:The obtained product is characterized by the following spectral data:
[a]23=-15,3°, (c = 1,26 CHCI3), (98% e.e.);[a] 23 = -15.3 °, (c = 1.26 CHCl 3), (98% ee);
1H NMR (CDCI3) δ: 2,93 (s, 1H, -OH); 3,56 (dd, 1H, J = 10,19; 8,56 Hz, jeden z -CH2-); 3,79 (dd, 1H, J = 10,19; 3,56 Hz, jeden z -CH2; 3,89 (s, 3H, -OCH3); 5,18 (dd, 1H, J = 8,56; 3,56 Hz -CHOH-); 6,92 (d, 1H, J = 8,17 Hz, H-3'); 7,02 (td, 1H, J = 7,53; 0,66 Hz, H-5'); 7,33 (td, 1H, J = 8,17; 1,62 Hz, H-4'); 7,47 (dd, 1H, J = 7,53; 1,62 Hz, H-6'). 1 H NMR (CDCl 3) δ: 2.93 (s, 1H, -OH); 3.56 (dd, 1H, J = 10.19; 8.56 Hz, one of -CH2-); 3.79 (dd, 1H, J = 10.19; 3.56 Hz, one of -CH2; 3.89 (s, 3H, -OCH3); 5.18 (dd, 1H, J = 8.56; 3.56 Hz -CHOH-); 6.92 (d, 1H, J = 8.17 Hz, H-3 '); 7.02 (td, 1H, J = 7.53; 0.66 Hz, H -5 '); 7.33 (td, 1H, J = 8.17, 1.62 Hz, H-4'); 7.47 (dd, 1H, J = 7.53, 1.62 Hz, H -6 ').
PL 228 397 Β1PL 228 397 Β1
Claims (3)
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| Application Number | Priority Date | Filing Date | Title |
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| PL407988A PL228397B1 (en) | 2014-04-24 | 2014-04-24 | Method for producing R-(-)-2-bromo-1-(2'-methoxyphenylo)-ethan-1-ol |
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| Application Number | Priority Date | Filing Date | Title |
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| PL407988A PL228397B1 (en) | 2014-04-24 | 2014-04-24 | Method for producing R-(-)-2-bromo-1-(2'-methoxyphenylo)-ethan-1-ol |
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| PL407988A1 PL407988A1 (en) | 2015-05-25 |
| PL228397B1 true PL228397B1 (en) | 2018-03-30 |
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