WO1988000190A1 - Optically active derivatives of glycidol - Google Patents
Optically active derivatives of glycidol Download PDFInfo
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- WO1988000190A1 WO1988000190A1 PCT/US1987/001523 US8701523W WO8800190A1 WO 1988000190 A1 WO1988000190 A1 WO 1988000190A1 US 8701523 W US8701523 W US 8701523W WO 8800190 A1 WO8800190 A1 WO 8800190A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
Definitions
- Optically active compounds have increasingly gained importance as the ability to manipulate the synthesis of other optically active compounds has improved.
- a compound is optically active if its atoms are not superimposable upon those of its mirror image.
- Isomers that are mirror images of each other are called enantiomers.
- Enantiomers have the same physical properties except for this difference in geometrical shape, i.e. mirror image. This difference however, has Important consequences.
- Obtaining asymmetric molecules has traditionally involved physically or chemically resolving the desired molecule from a racemic mixture of the two different optical forms.
- a second method the chiral pool method, involves using naturally occurring asymmetric molecules as building blocks for the desired asymmetric molecule.
- a third method has been developed which involves controlling the steps of the reaction so that only the desired enantiomer is produced (See U.S. Patent No. 4,471,130).
- the titanium-catalyzed asymmetric epoxidation of allylic alcohols has been important in further refining the above-described controlled step process.
- Homochiral glycidol has been useful in the synthesis of ⁇ -adrenergic blocking agents ( ⁇ -blockers).
- glycidol is difficult to store and isolate because it is unstable.
- the in situ derivation of glycidol where the unstable glycidol is derivatized after completion of the asymmetric epoxidation reaction rather than isolated directly from the reaction mixture has many benefits.
- the derivatives are easier to handle, and they are more advanced synthetic intermediates than the parent glycidol.
- the ability to obtain high enantiomeric purity for these glycidol derivatives can vary greatly. With many glycidol derivatives it has proven extremely difficult to improve the enantiomeric purity by crystallization.
- the (2S)-glycidyl m-nitrobenzenesulfonate preferably is purified to at least about 94% e.e., preferably at least about 96% e.e., and even more preferably at least about 98% e.e. Yields up to 98.8% e.e have been obtained in accord with this invention.
- the purity of the (2S)-glycidyl p-chlorobenzenesulfonate is preferably at least about 94% e.e. and more preferably at least about 95% e.e.
- This compound is preferably purified to at least about 90% e.e. and even more preferably to at least about 94% e.e.
- (2R)-glycidyl m-nitrobenzenesulfonate, (2R)-glycidyl ⁇ -chlorobenzenesulfonate and (2R)-glycidyl 4-chloro-3- nitrobenzenesulfonate can be similarly produced by using (+) -DIPT instead of (-)-DIPT.
- (2R) compounds can be purified to the same enantiomeric purity as (2S) compounds.
- the crystallized compound is stable and can easily be stored at room temperature until its use is desired.
- the stability of these compounds means that they can be used commercially as "starting materials" in the synthesis of, for example, ⁇ -blockers.
- starting materials for example, ⁇ -blockers.
- a convenient, one-pot procedure can be employed to convert the glycidyl m-nitrobenzenesulfonate into an important intermediate to the ⁇ -blocker, propranolol, which can be converted to propranolol by the addition of i PrNH 2 and H 2 O in the reaction mixture.
- X is m-nitro, p-chloro or 4-chloro-3- nltrobenzenesulfonate substituent
- ArOH is an aromatic alcohol. Any aromatic alcohol capable of displacing the sulfonate moiety can be used in the reaction to create the desired intermediate. Preferable aromatic alcohols are those that yield desired ⁇ -blockers upon subsequent reaction with a predetermined amine. The appropriate amine to use can be readily determined by the person of ordinary skill in the art.
- Crushed 3 ⁇ molecular sieves (Aldrich Chemical Co.) were activated by heating in a vacuum oven at 160oC and 0.05 mm Hg for at least 8 hours.
- Diisopropyl tartrate and titanium (IV) isopropoxide (Aldrich) were distilled under vacuum and were stored under an inert atmosphere. Allyl alcohol and cumene hydroperoxide (tech., 80%, Aldrich) were dried prior to use over 3 ⁇ molecular sieves, but otherwise used as received.
- Dichloromethane (EM Reagent) was not distilled, but was also dried over 3 ⁇ molecular sieves.
- 1-Naphthol (Aldrich) was sublimed prior to use.
- reaction mixture (stock solution A) (43 ml) was transferred into a 100-ml round-bottomed flask using a syringe, and triethylamine (4.2 ml, 2.05 g, 30 mmol) was added at -20°C, followed by addition of m-nitrobenzenesulfonyl chloride (4.43 g., 20 mmol) as a solution in 8 ml dichloromethane. The flask was stoppered and transferred to a freezer at -20oC.
- the reaction mixture was diluted with water (5 ml) and extracted with ether (3 x 10 ml). The combined extracts were washed with sat. brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude crystalline glycidyl 1-naphthyl ether (98.8% e.e.). The e.e. was determined by NMR analysis (DCI 3 ) of the Mosher ester, which was prepared from the crude glycidyl 1-naphthyl ether according to the method described in Example 1.
- (2S) -Glycidyl 4-chloro-3-nitrobenzenesulfonate was prepared using 4-chloro-3-nitrobenzenesulfonyl chloride instead of p-toluenesulfonyl chloride, according to the method described in Example 1.
- Crude crystals mp 49-54°C, 41% yield which were obtained by the crystallization of an oil from diethyl etherpet, ether mixture, were recrystallized from ethanol-ethyl acetate mixture to give pure crystals, mp 54.7-55.2°C, 94% e.e.
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Abstract
These compounds, (2S) and (2R) glycidyl m-nitrobenzenesulfonate, (2S) and (2R) glycidyl p-chlorobenzenesulfonate and (2S) and (2R) glycidyl 4-chloro-3-nitrobenzenesulfonate can be readily crystallized to high enantiomeric purity. Their use in other synthesis reactions is also described.
Description
OPTICALLY ACTIVE DERIVATIVES OF GLYCIDOL
Optically active compounds have increasingly gained importance as the ability to manipulate the synthesis of other optically active compounds has improved. A compound is optically active if its atoms are not superimposable upon those of its mirror image. Isomers that are mirror images of each other are called enantiomers. Enantiomers have the same physical properties except for this difference in geometrical shape, i.e. mirror image. This difference however, has Important consequences.
In living systems only one form of the stereoisomer generally functions properly. The other form typically either has no biological function or results in harm. In nature, the desired enantiomer is naturally synthesized. Synthetic chemists, in contrast, have rarely been as successful in making a pure enantiomer. They generally obtain racemic mixtures containing equal amounts of both optical forms of the molecule, i.e. dextrarotary (right-handed) and levorotary (left-handed). Consequently, these racemic mixtures do not exhibit properties based upon optical activity.
Obtaining asymmetric molecules has traditionally involved physically or chemically resolving the desired molecule from a racemic mixture of the two different optical forms. A second method, the chiral pool method, involves using naturally occurring asymmetric molecules as building blocks
for the desired asymmetric molecule. A third method has been developed which involves controlling the steps of the reaction so that only the desired enantiomer is produced (See U.S. Patent No. 4,471,130).
While the latter method has resulted in a tremendous advance in the field, problems still remain. The control over the reaction process is often not complete, and both forms of the molecule can still be produced. Even a small amount of the undesired form of the enantiomer results in significant loss of optical purity in the resultant mixture because an equal amount of the desired form of the enantiomer is associated with the undesired form. Thus, a step which produces 90% of the desired enantiomer only results in 80% enantiomeric excess (% e.e.).
The titanium-catalyzed asymmetric epoxidation of allylic alcohols has been important in further refining the above-described controlled step process. Homochiral glycidol has been useful in the synthesis of β-adrenergic blocking agents (β-blockers).
However, glycidol is difficult to store and isolate because it is unstable. The in situ derivation of glycidol where the unstable glycidol is derivatized after completion of the asymmetric epoxidation reaction rather than isolated directly from the reaction mixture has many benefits. The derivatives are easier to handle, and they are more advanced synthetic intermediates than the parent glycidol. However,
the ability to obtain high enantiomeric purity for these glycidol derivatives can vary greatly. With many glycidol derivatives it has proven extremely difficult to improve the enantiomeric purity by crystallization.
In substitution reactions of glycidol derivatives poor regioselectivity results in a substantial deterioration in the optical purity of the starting material. Consequently, it is desirable to find derivatives which approach optical purity, and which exhibit high regioselectivity in substitution reactions.
We have now discovered three compounds that are stable and can reach high enantiomeric purity. These compounds are (2S)-glycidyl m-nitrobenzenesulfonate, (2S)-glycidyl p-chlorobenzenesulfonate and glycidyl 4-chloro-3- nitrobenzenesulfonate. These compounds can readily be produced from allylic alcohol and crystallized to extremely high enantiomeric purity. With recrystallization it is possible to obtain enantiomeric purities in excess of 90%, and for the glycidyl m-nitrobenzenesulfonate up to about 99% e.e.
The compounds are produced by the following reaction schemes:
A. GLYCIDYL m-NITROBENZENESULFONATE
The (2S)-glycidyl m-nitrobenzenesulfonate preferably is purified to at least about 94% e.e., preferably at least about 96% e.e., and even more preferably at least about 98% e.e. Yields up to 98.8% e.e have been obtained in accord with this invention.
B. GLYGIDYL p-GHLOROBENZENESULFONATE
The purity of the (2S)-glycidyl p-chlorobenzenesulfonate is preferably at least about 94% e.e. and more preferably at least about 95% e.e.
C GLYCIDYL 4-CHLORO-3-NITROBENZENESULFONATE
(2R)-glycidyl m-nitrobenzenesulfonate, (2R)-glycidyl β-chlorobenzenesulfonate and (2R)-glycidyl 4-chloro-3- nitrobenzenesulfonate can be similarly produced by using (+) -DIPT instead of (-)-DIPT. (2R) compounds can be purified to the same enantiomeric purity as (2S) compounds.
Purification is obtained by using crystallization techniques which are well known in the art.
The crystallized compound is stable and can easily be stored at room temperature until its use is desired. The stability of these compounds means that they can be used commercially as "starting materials" in the synthesis of, for example, β-blockers. For example, a convenient, one-pot procedure can be employed to convert the glycidyl m-nitrobenzenesulfonate into an important intermediate to the β-blocker, propranolol, which can be converted to propranolol by the addition of iPrNH2 and H2O in the reaction mixture.
This substitution reaction takes place with extremely high regioselectivity, approaching 100:0 (C1:C3). The same reaction scheme can be used for converting the other compounds.
Other intermediates to β-blockers, or related compounds can be readily made according to the following reaction scheme:
The invention will be further illustrated by the examples that follow:
General
Crushed 3 Å molecular sieves (Aldrich Chemical Co.) were activated by heating in a vacuum oven at 160ºC and 0.05 mm Hg for at least 8 hours. Diisopropyl tartrate and titanium (IV) isopropoxide (Aldrich) were distilled under vacuum and were stored under an inert atmosphere. Allyl alcohol and cumene hydroperoxide (tech., 80%, Aldrich) were dried prior to use over 3 Å molecular sieves, but
otherwise used as received. Dichloromethane (EM Reagent) was not distilled, but was also dried over 3 Å molecular sieves. 1-Naphthol (Aldrich) was sublimed prior to use.
Melting points were determined on a Thomas Hoover capillary melting point apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer 597 spectrophotometer. 1H NMR spectra were recorded on a Bruker WM-250 (250 MHz) spectrometer with tetramethylsilane as an internal standard.
Example 1
Preparation of (2S) -Glycidyl m-nitrobenzenesulfonate.
An oven-dried 500-mL three-necked flask equipped with a magnetic stirrer, low-temperature thermometer, and rubber septums, was charged with activated 3 A powdered sieves (3.5 g) and 190 ml dichloromethane under nitrogen. D-(-)-Diisopropyl tartrate (DIPT) (1.40 g, 6mmol) was added via cannula as a solution in 1.5 ml CH2CI2, washing with an additional 1 ml CH2Cl2. Allyl alcohol (6.8 ml, 5.81 g, 0.1 mol) was then added, the mixture cooled to -5º C and Ti(OiPr)4 (1.50 ml, 1.43 g, 5 mraol) added via syringe. After stirring for 30 minutes, precooled (ice bath) cumene hydroperoxide (80%, 3.5 ml, ca. 0.2 mol) was added via cannula over a period of one hour, maintaining an internal temperature of ≤ 2ºC. The reaction mixture was stirred vigorously under nitrogen at -5 to 0ºC for six hours. After cooling to -20ºC trimethyl phosphite was added very
slowly via cannula, not allowing the temperature to rise above -10ºC, and carefully monitoring the reduction of hydroperoxide [TLC in 40% EtOAc/hexane; tetramethyl phenylenediamine spray Indicator (1.5 g in MeOH:H2O:HOAc 128:25:1 ml); ca. 14.1 ml (14.89 g, 0.12 moles) of P(OMe)3 were required for complete reduction. Further excess should be avoided.] The reaction is quite exothermic and addition took one hour resulting in formation of stock solution A.
One fifth of the reaction mixture (stock solution A) (43 ml) was transferred into a 100-ml round-bottomed flask using a syringe, and triethylamine (4.2 ml, 2.05 g, 30 mmol) was added at -20°C, followed by addition of m-nitrobenzenesulfonyl chloride (4.43 g., 20 mmol) as a solution in 8 ml dichloromethane. The flask was stoppered and transferred to a freezer at -20ºC.
After 10 hours the reaction mixture was allowed to warm gradually to room temperature, then filtered through a pad of Celite, washing with additional dichloromethane. The resultant yellow solution was washed with 10% tartaric acid, followed by sat. brine, dried (MgSO4) and concentrated to afford an oil, from which volatile components (e.g. cumene, 2-phenyl-2-propanol, P(OMe)3, OP(OMe)3,etc.) were removed under high vacuum at 65ºC on a rotary evaporator equipped with a dry ice condenser. The residue was filtered through a short pad of silica gel (ca. 1 g per g crude oil), elutlng with dichloromethane. Concentration gave a lemon yellow oil which was dissolved in ca. 18 ml warm Et2O and crystallized
by addition of hexane to give 2.932 g (56.6% yield) of
(2S)-glycidyl m-nitrobenzenesulfonate, m.p. 54-60ºC (96% e.e.).
Attempts to measure the e.e. directly, via 1H NMR in the presence of chiral shift reagents, or by HPLC on a chiral stationary phase, proved unsuccessful. Therefore, glycidyl m-nitrobenzenesulfonate was converted to the corresponding iodohydrin, following Conforth's published procedure (J. Chem. Soc. (1959), 112). The crude iodohydrin was then directly esterified with (R)-(+)-α-methoxy-α- (trifluoromethyl) phenylacetyl chloride to give the Mosher ester, and the e.e. measurement was made by HPLC of the ester on a chiral Pirkle column, eluting with 8% iso-proponal/hexane. The e.e. was also determined by H NMR analysis of the Mosher ester in G6D6.
A part of the crystals (2.635 g) was recrystallized twice from ethanol to afford 1.745 g of pure crystals, m.p. 63-64ºC; α + 23.0 (C-2.14, CHCI3); 99% e.e.
IR (KBr) 3114, 3090, 1611, 1532, 1469, 1451, 1428, 1354, 1280, 1257, 1188, 1132, 1086, 1076, 1004, 981, 963, 919, 913, 889, 867, 842, 820, 758, 739, 674, 667, 596, 585, 549, 524, 447, 430, 405 cm-1.
NMR (250 MHz, CDCI3) δ 8.79 (t, J=1.5 Hz, 1H),
8.54 (m, 1H), 8.28 (m, 1H),
7.82 (t, J=8.0, 8.0 Hz, 1H),
4.50 (dd, J=3.4, 11.4 Hz, 1H).
4.04 (dd, J=6.0, 11.4Hz, 1H),
3.23 (m, 1H), 2.86 (t, J=4.5, 4.5 Hz, 1H)
2.64 (dd, J=2.5, 4.75 Hz, 1H).
Example 2
Substitution Reaction.
In a 5-ml round-bottomed flask equipped with a rubber septum, sodium hydride (oil free, 24 mg, 1 mmol) was suspended in DMF (1 ml, stored over 3k sieves) at room temperature under a nitrogen atmosphere. 1-Naphthol (121 mg,
0.84 mmol) was added as a solution in DMF (0.5 ml) to produce a foamy green sludge. After 15-30 minutes, a solution of
(2S)-glycidyl m-nitrobenzenesulfonate (98.8% e.e., 207 mg, 1 mmol In 0.5 ml DMF) was added. A clear green-brown solution resulted.
After 30 minutes the reaction was judged to be complete by TLC (silica gel, 40% EtOAc/hexane).
The reaction mixture was diluted with water (5 ml) and extracted with ether (3 x 10 ml). The combined extracts were washed with sat. brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude crystalline glycidyl 1-naphthyl ether (98.8% e.e.). The e.e. was determined by NMR analysis (DCI3) of the
Mosher ester, which was prepared from the crude glycidyl 1-naphthyl ether according to the method described in Example 1.
Example 3
Preparation of (2S)-glycidyl p-chlorobenzenesulfonate.
One fifth of stock solution A (43 ml) from Example 1 was transferred into a 100 ml round-bottomed flask using a syringe, and triethylamine (4.2 ml, 3.05 g, 30 mmol) was added at -20°C, followed by the addition of p-chlorobenzenesulfonyl chloride (4.22 g, 20 mmol). Thereafter, the (2S)-glycidyl p-chlorobenzenesulfonate was prepared according to the procedure of Example 1.
The crystals were obtained by crystallization of the extracts from ether-hexane (37.5% yield), m.p. 60.7-62.3ºC
(94% e.e.), which was recrystallized from ethanol-hexane to afford pure crystals, m.p. 61-62.5ºC; +
22.6 (C=2.02, CHCl3); 95.2% e.e.
IR (KBr) 3100, 1572, 1478, 1452, 1399, 1360
1281, 1260, 1180, 1136, 1089, 1019,
960, 917, 868, 826, 770, 754, 709,
628, 576, 531, 489, 448 cm"1.
NMR (250 MHz, CDCI3) δ 7.87 (d, J=8.0 Hz, 2H),
7.55 (d, J=8.0 Hz, 2H) , 4.34 (dd, J=3.4, 11.4 Hz, 1H), 3.97 (dd, J=6.0, 11.4 Hz, 1H), 3.21 (m, 1H), 2.84 (t, J=4.5, 4.5 Hz, 1H), 2.62 (dd, J=2.5, 4.75 Hz, 1H).
Example 4
Preparation of (2S)-glycidyl 4-ehloro-3- nitrobenzenesulfonafce
(2S) -Glycidyl 4-chloro-3-nitrobenzenesulfonate was prepared using 4-chloro-3-nitrobenzenesulfonyl chloride instead of p-toluenesulfonyl chloride, according to the method described in Example 1. Crude crystals (mp 49-54°C, 41% yield) which were obtained by the crystallization of an oil from diethyl etherpet, ether mixture, were recrystallized from ethanol-ethyl acetate mixture to give pure crystals, mp 54.7-55.2°C, 94% e.e.
The preparation of the Mosher ester and the ee measurement of the ester were made according to the method described in Example 1.
IR(KBr) 3105, 3015, 1605, 1573, 1541, 1454, 1400, 1385, 1363,
1339, 1252, 1197, 1190, 1170, 1159, 1107, 1056, 995, 979, 963,
945, 922, 914, 899, 868, 842. 779, 767. 759, 670, 647, 591, 576,
533, 494, 452, cm-1.
NMR (250 MHz, CDU3) δ 8.43 (d, J=2Hz, 1H), 8.05 (dd,
J=2.1, 8.5 Hz, 1H), 7.79 (d, J=8.5, 1H) 4.51 (dd, J=2.8, 11.6
Hz, 1H) 4.04 (dd, J=6.5, 11.6 Hz, 1H) 3.23 (m, 1H), 2.87 (t,
J=4.5, 4.5 Hz, 1H) 2.6 (dd, J=2.5, 4.4Hz, 1H) .
This invention has been described in detail including the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of this
disclosure, may make modifications and improvements thereon without departing from the spirit and scope of the invention as set forth in the claims.
Claims
1. A compound of the formula
2. The compound of claim 1 purified to have an enantiomeric purity of at least about 96% e.e.
3. The compound of claim 2 purified to at least about 98.8% e.e.
4. The compound of claim 2 produced from an allyllc alcohol.
5. A compound of the formula
6. The compound of claim 5 purified to have an enantiomeric purity of at least about 96% e.e.
7. The compound of claim 6 purified to at least about 98.8% e.e.
8. The compound of claim 6 produced from an allylic alcohol.
9. A compound of the formula
10. The compound of claim 7 purified to at least about 95.0% e.e.
11. The compound of claim 10 produced from an allylic alcohol.
12. A compound of the formula
13. The compound of claim 12 purified to at least about 95.0% e.e.
14. The compound of claim 12 produced from an allylic alcohol.
15. A compound of the formula
16. The compound of claim 15 purified to at least about 90% e.e.
17. The compound of claim 16 purified to at least about 94% e.e.
18. The compund of claim 16 produced from an allylic alcohol.
19. A compound of the formula
20. The compound of claim 19 purified to at least about 90% e.e.
21. The compound of claim 20 purified to at least 94% e.e.
22. The compound of claim 19 produced from an allylic alcohol.
23. A compound of the formula
24. The compound of claim 15 recrystallized to an optical purity of at least about 98.8% e.e.
25. A compound of the formula
26. A compound of the formula
produced from a mixture containing its enantiomer wherein the compound has been recrystallized to an optical purity of at least about 96.0% e.e.
27. The compound of claim 15 recrystallized to an optical purity of at least about 98.8% e.e.
28. The compound of the formula
produced from a mixture containing its enantiomer wherein the compound has been recrystallized to an optical purity of at least about 95.0% e.e.
29. A compound of the formula
30. The compound of claim 27 purified to an optical purity of at least about 94% e.e.
31. A compound of the formula
32. The compound of claim 29 purified to an optical purity of at least about 94% e.e.
33. A method for making a β- locker, said method comprising reacting glycidyl m-nitrobenzenesulfonate, glycidyl p-chlorobenzenesulfonate or glycidyl 4-chloro-3-nitrobenzenesulfonate with a suitable aromatic alcohol, ArOH, to displace the nitrobenzenesulfonate, the chlorobenzenesulfonate moiety or the 4-chloro-3- nitrobenzenesulfonate moiety and replace it with ArO-moiety, where Ar is any aromatic group and thereafter reacting the thus formed intermediate, with a predetermined amine.
34. The method of claim 7 wherein the aromatic alcohol, ArOH, is 1-naphthol.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US87817686A | 1986-06-25 | 1986-06-25 | |
| US878,176 | 1986-06-25 | ||
| US913,936 | 1986-10-01 | ||
| US07/913,936 US4946974A (en) | 1986-10-01 | 1986-10-01 | Optically active derivatives of glycidol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1988000190A1 true WO1988000190A1 (en) | 1988-01-14 |
Family
ID=27128478
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1987/001523 Ceased WO1988000190A1 (en) | 1986-06-25 | 1987-06-24 | Optically active derivatives of glycidol |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA1340738C (en) |
| WO (1) | WO1988000190A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991010642A1 (en) * | 1990-01-22 | 1991-07-25 | Nobel Chemicals Ab | Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates prepared in accordance with this process |
| EP0441471A1 (en) * | 1990-01-26 | 1991-08-14 | Zeneca Limited | Optical resolution |
| WO1993004054A1 (en) * | 1991-08-22 | 1993-03-04 | Syracuse University | Method and apparatus for synthesis of highly isomerically pure stereoisomers of glycidol derivatives |
| US8703948B2 (en) | 2006-11-28 | 2014-04-22 | Janssen Pharmaceutica Nv | Salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one |
| US8741916B2 (en) | 2007-04-09 | 2014-06-03 | Janssen Pharmaceutica Nv | 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the ORL-1 receptor |
| US8778956B2 (en) | 2002-09-09 | 2014-07-15 | Janssen Pharmaceutica Nv | Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders |
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| WO1991010642A1 (en) * | 1990-01-22 | 1991-07-25 | Nobel Chemicals Ab | Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates prepared in accordance with this process |
| EP0441471A1 (en) * | 1990-01-26 | 1991-08-14 | Zeneca Limited | Optical resolution |
| WO1993004054A1 (en) * | 1991-08-22 | 1993-03-04 | Syracuse University | Method and apparatus for synthesis of highly isomerically pure stereoisomers of glycidol derivatives |
| US8778956B2 (en) | 2002-09-09 | 2014-07-15 | Janssen Pharmaceutica Nv | Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders |
| US8703948B2 (en) | 2006-11-28 | 2014-04-22 | Janssen Pharmaceutica Nv | Salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one |
| US8741916B2 (en) | 2007-04-09 | 2014-06-03 | Janssen Pharmaceutica Nv | 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the ORL-1 receptor |
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