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WO1998030540A1 - Synthese efficace d'un mediateur chiral - Google Patents

Synthese efficace d'un mediateur chiral Download PDF

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Publication number
WO1998030540A1
WO1998030540A1 PCT/US1998/000578 US9800578W WO9830540A1 WO 1998030540 A1 WO1998030540 A1 WO 1998030540A1 US 9800578 W US9800578 W US 9800578W WO 9830540 A1 WO9830540 A1 WO 9830540A1
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WO
WIPO (PCT)
Prior art keywords
compound
recited
formula
phenyl
enantiomer
Prior art date
Application number
PCT/US1998/000578
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English (en)
Inventor
Cheng Yi Chen
Feng Xu
Richard D. Tillyer
Dalian Zhao
Original Assignee
Merck & Co., Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9704194.1A external-priority patent/GB9704194D0/en
Priority claimed from GBGB9710393.1A external-priority patent/GB9710393D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU60225/98A priority Critical patent/AU732430B2/en
Priority to CA002276074A priority patent/CA2276074A1/fr
Priority to EP98903459A priority patent/EP0973737A4/fr
Priority to JP10531222A priority patent/JP2000507970A/ja
Publication of WO1998030540A1 publication Critical patent/WO1998030540A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the instant invention discloses an efficient method for the quantitative preparation and isolation of the enantiomers of the compound of formula I I
  • the present invention concerns a novel process for the preparation of a compound of formula I
  • the present invention also concerns compounds of Formula I as chiral mediators useful in enantioselective synthesis.
  • An example of a compound of Formula I is (1R,2S)-N- pyrrolidinyl norephedrine, which is a chiral mediator used in an enantioselective addition reaction.
  • the preparation of [R-(R*,S*)]- ⁇ - methyl- - ⁇ henyl-1-pyrrolidineethanol in quantitative yield was accomplished by alkylation of (lR,2S)-(-)-norephedrine with 1,4- dibromobutane in toluene using NaHC ⁇ 3 as base.
  • the instant invention relates to a method for the preparation of a compound of Formula I
  • n 1, 2, or 3;
  • n 0, or 1 ;
  • R! is: H, phenyl, or Cl-C6-alkyl, unsubstituted or substituted with Cl-C6-alkoxy;
  • R2 is: H, Cl-C6-alkyl, or
  • R 3 is: H, C ⁇ -C6-alkyl, or phenyl
  • R4 is: H, except that Rl and R4 can represent a carbon carbon bond, when t is lor 2, or — (CH2)s — » when t is 0;
  • step (a) wherein the base is selected from the group consisting of: Li2C ⁇ 3, Na2C ⁇ 3, K2CO3, L1HCO3, NaHC ⁇ 3, KHCO3, LiOH, NaOH, and KOH.
  • step (a) wherein the solvent is selected from the group consisting of: toluene, heptane, n- butanol, methylcyclohexane, and tetrahydrofuran.
  • step (a) wherein (1R,2S)- (-)-norephedrine to alkylating agent ratio is about a 1 to 1.1 ratio.
  • step (a) wherein the dihalide to base ratio is about a 1 to 2 ratio.
  • step (a) wherein the base is preferably KHCO3, NaHC ⁇ 3, K2CO3, and Na2C ⁇ 3.
  • step (a) wherein the solvent system is toluene.
  • step (a) wherein the reaction temperature is about 105° to about 118°C.
  • step (a) wherein the reaction time is about 18 to about 24 hours.
  • step (a) wherein (1R,2S)- norephedrine to 1 ,4-dibromobutane ratio is about a 1 to 1.1 ratio.
  • step (a) wherein the 1,4- dibromobutane to NaHC ⁇ 3 is about a 1 to 2 ratio.
  • step (a) wherein the reaction temperature is about 105° to about 118°C.
  • ⁇ / ⁇ represents a six-membered ring, unsaturated or saturated, optionally substituted with one or two heteroatoms selected from N, O, or S, optionally substituted with Cl-C6-alkyl;
  • n 1, 2, or 3;
  • n 0, or 1;
  • t 0, 1, or 2;
  • s 1 or 2;
  • R! is: H, phenyl, or Cl-C6-alkyl, unsubstituted or substituted with Cl-C6-alkoxy;
  • R is: H, Cl-C6-alkyl, or
  • R3 is: H, Cl-C6-alkyl, or phenyl
  • R4 is: H, except that Rl and R4 can represent a carbon carbon bond, when t is lor 2, or — (CH2)s — , when t is 0,
  • Rl is H or CH3, that A cannot represent
  • A cannot represent — (CHR3) n — , when n is 2, and R3 is H, as a free base or an acid salt thereof.
  • An acid salt such as a salt of an organic acid or inorganic acid.
  • organic acids capable of forming an acid salt include but are not limited to: citric acid, acetic acid, trifluoroacetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, and benzoic acid.
  • inorganic acids capable of forming an acid salt include but are not limited to: HC1, HBr, H3PO4 and H2SO4.
  • A represents:
  • -/ 5 ⁇ represents: a five-membered ring, unsaturated or saturated, optionally substituted with one or two heteroatoms selected from N, O, or S, optionally substituted with Cl-C6-alkyl;
  • n 1, 2, or 3;
  • n 0, or 1 ;
  • t 0, 1, or 2;
  • s 1 or 2;
  • R! is: H, phenyl, or Cl-C6-alkyl, unsubstituted or substituted with Cl-C6-alkoxy;
  • R 2 is: H, Cl-C6-alkyl, or
  • R 3 is: H, Cl-C6-alkyl, or phenyl
  • R4 is: H, except that Rl and R4 can represent a carbon carbon bond, when t is lor 2, or — (CH2)s — , when t is 0;
  • step (e) wherein the solvent is selected from the group consisting of: toluene, heptane, n-butanol, methylcyclohexane and tetrahydrofuran.
  • step (e) wherein the aqueous acid solution is selected from the group consisting of: an aqueous inorganic acid solution and an aqueous organic acid solution.
  • step (a) wherein aminoalcohol compound to dihalide ratio is about 1 to about 1.1 ratio.
  • step (a) wherein the dihalide to base ratio is about 1 to about 2 ratio.
  • step (a) wherein the base is selected from the group consisting of: KHCO3, NaHC ⁇ 3, K2CO3, and Na2C ⁇ 3.
  • aqueous acid solution is an aqueous inorganic acid solution selected from the group consisting of: HC1, HBr, H3PO4 and H2SO4.
  • aqueous acid solution is an aqueous organic acid solution selected from the group consisting of: citric acid, acetic acid, trifluoroacetic acid, maleic acid, methylsulfonic acid, p-toluenesulfonic acid, formic acid, and benzoic acid.
  • step (a) wherein the reaction temperature is about 105° to about 118°C.
  • step (a) wherein the reaction time is about 18 to about 24 hours.
  • step (e) wherein the aqueous acid solution is citric acid.
  • step (g) wherein the base is selected from the group consisting of: aqueous LiOH, KOH and NaOH.
  • the compound of Formula I is selected from the group consisting of:
  • [R-(R*,S*)]- ⁇ -methyl- ⁇ -phenyl-l-py ⁇ olidineethanol also referred to as (1R,2S )- ⁇ -pyrrolidinylnorephedrine
  • (1R,2S )- ⁇ -pyrrolidinylnorephedrine is an important chiral mediator for the enantioselective addition of an acetylide to a prochiral ketone.
  • alkylating agent useful in this method are: 1,3-dibromopropane, 1 ,4-dibromobutane, 1,5-dibromo ⁇ entane, (2- bromomethyl)benzylbromide, 2-(2-bromoethyl)benzylbromide, 1,2- di(bromomethyl)naphthalene, 2,3-di(bromomethyl)naphthalene, 1,8- di(bromomethyl)naphthalene, etc.
  • heterocyclic alkylating agents are: [2,3-di(bromomethyl)]pyridine, [3,4- di(bromomethyl)]-pyridine, 2-(2-bromoethyl)-3-bromomethylpyridine, 3-(2-bromoethyl)-2-bromomethylpyridine, 3-(2-bromoethyl)-4- bromomethylpyridine, 4-(2-bromoethyl)-3-bromomethylpyridine, 3-(2- bromoethyl)-4-bromomethyl-pyridine, etc.
  • chloride, iodide, tosylate, mesylate and triflate analogs of the aforementioned alkylating agents are: Li2C ⁇ 3, Na2C ⁇ 3,
  • the solvent systems useful in this method are: toluene, heptane, n-butanol, tetrahydrofuran.
  • the preferred base-solvent system was NaHC03- toluene, which allowed for the isolation of the chiral mediator in crystalline form in qualitative yield.
  • the actual compound used in the chiral addition reaction is the free base, which is generated in situ prior to use in the addition reaction.
  • Step A Preparation of [R-(R*,S*)]- ⁇ -methyl- ⁇ -phenyl-l- pyrrolidineethanol Under nitrogen, to a 22 L three-necked round bottom flask equipped with a mechanical stirrer, a condenser with Dean-Stark trap and a thermocouple was charged with toluene (8 L), (1R,2S )-(-)- norephedrine (1.512 kg, 10 mol), 1 ,4-dibromobutane (2.375 kg, 11
  • HPLC conditions HPLC Column: 4.6 mm x 25 cm Inertsil phenyl Eluent A: MeCN; Eluent B: pH 6.0 phosphate buffer, 15 mM (8.28 g NaH2P ⁇ 4-H2 ⁇ and 0.8 mL Et3N in 4 L HPLC grade water); Gradient: 14% A kept for 5 min then changed to 44% A over 11 min and kept this ratio for another 6min; Injection: 20 ⁇ L; Flow rate: 1.5 mL/min; Detection: 210 nm; Temperature: 23 °C; and Retention Times: Sodium bromide: 1.8 min; Norephedrine: 5.0 min; Product: 12.0 min; Toluene: 22.5 min. 4.
  • the main purpose here is to remove most of the water in the toluene solution because the water in toluene solution would interfere the HC1 salt formation, lowering the recovery of the salt product.
  • Step B Preparation of [R-(R*,S*)]- ⁇ -methyl- ⁇ -phenyl-l- pyrrolidineethanol hydrochloride
  • the batch volume of the organic layer from Step A was then adjusted to 10 L with toluene and cooled to 10-15°C with ice-water bath.
  • HC1 in IPA (2.56 L, 4.3 N) was added to the toluene solution slowly over a period of about 50 minutes, keeping the batch temperature below 25°C (note 6).
  • the batch was aged at ambient temperature for 1 h and isopropyl alcohol was removed by azeotropic distillation (Note 7).
  • the batch was flushed with toluene (2x2 L) until the concentration of the product in supernatant was less than 3 g/L.
  • the batch was then cooled to 15°C and aged at this temperature for 1 h.
  • the HC1 salt was isolated by filtration and the wet cake was washed with toluene (2x2.5 L). The product loss in combined filtrate and wash was less than 1%.
  • Step C Isolation of [R-(R*,S*)]- ⁇ -methyl- ⁇ -phenyl-l- pyrrolidineethanol
  • HPLC sample preparation 50 ⁇ L filtered clear reaction solution (Whatman syringe filter 0.45 ⁇ M PTFE) was dissolved in 50/50 MeCN/water to 50 mL.
  • the ratio of the product to starting material norephedrine HPLC area percentage should be around 94.5:5.5 or higher.
  • the level of 1 ,4-dibromobutane (the ratio to product should be less than 0.8 mole%) could be determined by proton NMR or GC (GC method hasn't been developed yet).
  • the batch was cooled to ambient temperature, filtered through a sintered glass funnel to remove solid sodium bromide salt.
  • the wet cake was washed with 300 mL toluene.
  • the combined filtrate and wash was washed with D.I. water 2x400 mL.
  • the top organic layer was then concentrated on a rotavap to around 400 mL (1/3 of the original total volume).
  • Step B Preparation of [R-(R*,S*)]- ⁇ -methyl- -phenyl-l- pyrrolidineethanol Hydrochloride
  • the batch was then transferred back to the reaction flask and adjusted to 800 mL with toluene. It was cooled to 10-15°C with ice- water bath and HCl in IPA (260 mL, 4.5 N) was added slowly in 30 min while kept the batch temperature below 25°C. The batch was aged at
  • Step C Isolation of [R-(R*,S*)]- ⁇ -methyl- ⁇ - ⁇ henyl-l- pyrrolidineethanol
  • the wet cake was transferred to a separatory funnel, 800 mL toluene and 700 mL 1.5 N NaOH were added (no obvious exothermic observed). Two phases were mixed well and layers were separated. The aqueous layer (pH>12) was extracted with toluene 2x500 mL. The combined organic layer was concentrated on a rotavap and flushed with toluene 1x500 mL. The final batch volume was adjusted to about 500 mL. The final solution gave [R-(R*,S*)]- ⁇ -methyl- ⁇ -phenyl- 1 -pyrrolidineethanol (212 g) in toluene as a light yellow solution (45wt%) with 95% yield.
  • HPLC Conditions Column: 4.6 mm x 25 cm Inertsil phenyl;
  • Eluent A MeCN
  • Eluent B pH6.0 phosphate buffer [15 mM (8.28 g NaH 2 P ⁇ 4-H2 ⁇ and 0.8 mL Et3N in 4 L HPLC grade water)];
  • the batch was cooled to ambient temperature, filtered through a sintered glass funnel to remove solid sodium bromide salt.
  • the wet cake was washed with 3 L toluene.
  • the combined filtrate and wash was washed with D.I. water 1 x 6 L (the product in aqueous layer loss was less than 1%).
  • the organic layer was transferred to a 50 L extractor and extracted with 30% aqueous citric acid solution at room temperature. The mixture was stirred for 15 min and the layers were separated. The aqueous layer was transferred back to the extractor which contained 10 L toluene. 50 w/w% NaOH (3.57 kg) was added slowly so that the temperature was kept below 30 °C. The mixture was stirred for 15 min and the layers were separated, (the pH of the aqueous layer was 12-12.5). The aqueous layer was extracted with toluene once (1x5 L). The aqueous layer was removed and combined organic layers were washed with D.I. water twice (2x5 L).
  • the washed organic layer was concentrated with vacuum and the batch volume was reduced to about 6-8 L.
  • the batch was then flushed with toluene 2x3 L.
  • the final batch volume was adjusted to about 5 L which gave the product (1.97 kg) in toluene as a light yellow solution (38 wt%) with 96% yield.
  • the solution KF was 80-100 ⁇ g/mL.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Lasers (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne un procédé efficace de préparation quantitative et d'isolement d'un composé de formule (I) ou de son énantiomère, lequel est un médiateur chiral utilisé dans une synthèse énantiosélective.
PCT/US1998/000578 1997-01-10 1998-01-06 Synthese efficace d'un mediateur chiral WO1998030540A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU60225/98A AU732430B2 (en) 1997-01-10 1998-01-06 Efficient synthesis of a chiral mediator
CA002276074A CA2276074A1 (fr) 1997-01-10 1998-01-06 Synthese efficace d'un mediateur chiral
EP98903459A EP0973737A4 (fr) 1997-01-10 1998-01-06 Synthese efficace d'un mediateur chiral
JP10531222A JP2000507970A (ja) 1997-01-10 1998-01-06 キラルメディエータの効率的な合成

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US3492697P 1997-01-10 1997-01-10
US60/034,926 1997-01-10
GBGB9704194.1A GB9704194D0 (en) 1997-02-28 1997-02-28 Efficient synthesis of a chiral mediator
US4202197P 1997-04-17 1997-04-17
US60/042,021 1997-04-17
US4516797P 1997-04-30 1997-04-30
US60/045,167 1997-04-30
GBGB9710393.1A GB9710393D0 (en) 1997-05-20 1997-05-20 Efficient synthesis of a chiral mediator
GB9704194.1 1997-05-20
GB9710393.1 1997-05-20

Publications (1)

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WO1998030540A1 true WO1998030540A1 (fr) 1998-07-16

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Country Status (5)

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EP (1) EP0973737A4 (fr)
JP (1) JP2000507970A (fr)
AU (1) AU732430B2 (fr)
CA (1) CA2276074A1 (fr)
WO (1) WO1998030540A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6015926A (en) * 1997-05-16 2000-01-18 Merck & Co., Inc. Efficient enantioselective addition reaction using an organozinc reagent
US8115032B2 (en) 2009-04-09 2012-02-14 Lonza Ltd. Process for the synthesis of a propargylic alcohol
WO2012048887A1 (fr) 2010-10-14 2012-04-19 Lonza Ltd Procédé de synthèse de d'alcools propargyliques chiraux cycliques
WO2012048884A1 (fr) 2010-10-14 2012-04-19 Lonza Ltd Procédé de synthèse de carbamates cycliques
US8283502B2 (en) 2009-04-09 2012-10-09 Lonza Ltd. Autocatalytic process for the synthesis of chiral propargylic alcohols

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DE10019879A1 (de) * 2000-04-20 2001-10-25 Degussa Verfahren zur Herstellung von 2,5-Diketopiperazinen, neue 2,5-Diketopiperazine und deren Verwendung

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US3028378A (en) * 1962-04-03 Pharmacologically active compounds
US2552502A (en) * 1947-09-11 1951-05-08 Upjohn Co Beta-(pyrrolidyl-1)-propanol-2
US2723269A (en) * 1949-11-03 1955-11-08 American Cyanamid Co Piperidino tertiary amino alcohols
US2975193A (en) * 1959-06-18 1961-03-14 Parke Davis & Co Organic amine compounds and method of obtaining the same
US3468893A (en) * 1966-03-14 1969-09-23 Ciba Geigy Corp 1-substituted-diphenyl-azacycloalkenes
US3754003A (en) * 1971-07-08 1973-08-21 A Pedrazzoli Tetramethyl pyrrolidine derivatives

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DATABASE STN CAPLUS 1 January 1900 (1900-01-01), AZIZOV A M, ET AL: "COMPLETE ALKYLATION OF 2-AMINOETHANOL IN THE PRESENCE OF SODIUM HYDROXIDE", XP002912387, Database accession no. 1987:137905 *
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6015926A (en) * 1997-05-16 2000-01-18 Merck & Co., Inc. Efficient enantioselective addition reaction using an organozinc reagent
US8115032B2 (en) 2009-04-09 2012-02-14 Lonza Ltd. Process for the synthesis of a propargylic alcohol
US8283502B2 (en) 2009-04-09 2012-10-09 Lonza Ltd. Autocatalytic process for the synthesis of chiral propargylic alcohols
WO2012048887A1 (fr) 2010-10-14 2012-04-19 Lonza Ltd Procédé de synthèse de d'alcools propargyliques chiraux cycliques
WO2012048884A1 (fr) 2010-10-14 2012-04-19 Lonza Ltd Procédé de synthèse de carbamates cycliques
EP2447255A1 (fr) 2010-10-14 2012-05-02 Lonza Ltd. Processus de synthèse de carbamates cycliques
EP2447247A1 (fr) 2010-10-14 2012-05-02 Lonza Ltd. Processus pour la synthèse d'alcools propargyliques chiraux
US8957204B2 (en) 2010-10-14 2015-02-17 Lonza Ltd. Process for the synthesis of cyclic carbamates

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EP0973737A4 (fr) 2000-04-26
CA2276074A1 (fr) 1998-07-16
JP2000507970A (ja) 2000-06-27
AU6022598A (en) 1998-08-03
EP0973737A1 (fr) 2000-01-26
AU732430B2 (en) 2001-04-26

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