EP1210334A1 - Process of making imidazolidine-2-one derivatives - Google Patents

Process of making imidazolidine-2-one derivatives

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Publication number
EP1210334A1
EP1210334A1 EP00947137A EP00947137A EP1210334A1 EP 1210334 A1 EP1210334 A1 EP 1210334A1 EP 00947137 A EP00947137 A EP 00947137A EP 00947137 A EP00947137 A EP 00947137A EP 1210334 A1 EP1210334 A1 EP 1210334A1
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EP
European Patent Office
Prior art keywords
phenyl
galkyl
compound
formula
substituted
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00947137A
Other languages
German (de)
French (fr)
Other versions
EP1210334A4 (en
Inventor
Lendon N. Pridgen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
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SmithKline Beecham Corp
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Filing date
Publication date
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Publication of EP1210334A1 publication Critical patent/EP1210334A1/en
Publication of EP1210334A4 publication Critical patent/EP1210334A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom

Definitions

  • the present invention relates to a process to prepare chiral auxiliary intermediates which are useful in the asymmetric syntheses of useful organic compounds. These auxiliaries are imidizolidin-2-ones. Of particular importance, the present invention relates to any improvement in the process to prepare aromatic ring-fused cyclopentane derivatives, specifically indane-2-carboxylates and cyclopentano[b]pyridino-2-carboxylates. This improvement relates to the process for preparing important chiral intermediates used in the preparation of indanes and cyclopentano[b]pyridines. This chiral intermediate is (4R,5S)- l,5-dimethyl-4-phenyl-imidizolidin-2-one.
  • chiral auxiliary means a non-racemic functional group that imparts a distereoselective reaction at a remote prochiral center of a molecule.
  • Chiral auxiliary intermediates which are useful in such synthesis are known in the art. These include l,3-oxazolidin-2-ones, see Soloshonok et al., Org. Letters, 747(2000) and reviews noted therein, and imidiazolidin-2-ones, see Bongini et al., Tetrahedron: Asymmetry, 1996, 1457 and references therein. All information within these references necessary to understand and use this invention are incorporated by reference.
  • the chiral intermediate (4R,5S)- l,5-dimethyl-4-phenyl-imidizolin-2-one is one of these important auxiliaries useful to prepare pharmaceutically active compounds.
  • Other structurally related iminidazolin-2-ones, including its enantiomer, are also useful.
  • the known literature procedures to make these compounds have a number of problems.
  • An improved method to prepare these auxiliaries was desired. I have now found and disclose useful improvements to the process to prepare these clinical auxiliary intermediates. More specifically, these process improvements can be used to prepare certain endothelin receptor antagonists.
  • Certain indane-2-carboxylic acids and cyclopentano[6]pyridines are useful endothelin receptor antagonists; see U.S. Patent Nos.
  • the process of this invention involves the following process:
  • Ri is Ci .galkyl, cyclohexyl, phenyl, phenyl substituted with Ci .galkyl, halo, nitro, Ci .galkoxy, Ci.galkylmercapto or CF3, napthyl or napthyl substituted with C i.galkyl, halo, nitro, Ci .galkoxy or CF3;
  • R2 is Ci.galkyl, C i.galkenyl, cyclohexyl, phenyl, or phenylCi .galkyl wherein each phenyl may be substituted with one or two substituents selected from nitro, Ci .galkoxy, methylenedioxy or CF3; and
  • R3 is C i.galkyl, C i .galkenyl, C3_gcycloalkyl, phenyl or phenylCi .galkyl wherein each phenyl may be substituted with one or two substituents selected from nitro, Ci.galkyl, halo, nitro, Cj.galkoxyl, methylenedioxy, CF3 or dialkylamino, and urea together in the presence of a non- volatile ammonium salt.
  • R 1 a preferred group are those moieties which provide steric bulk such as phenyl, substituted phenyl, napthyl and substituted napthyl. Particularly preferred is phenyl.
  • R2 and R3 groups are alkyl, phenyl or phenylalkyl.
  • halo means fluoro, bromo or chloro and alkyl means straight or branched chained alkyl groups.
  • Suitable ammonium salts include, but are not limited to, ammonium sulfamate, ammonium sulfate, and ammonium dihydrogen phosphate. Other suitable ammonium salts can be readily determined by one skilled in the art. A preferred ammonium salt is ammonium sulfamate.
  • the process is run at a temperature of 75°-190°C.
  • the reaction is run in the beginning in an inert organic solvent with a boiling point greater than 75°C in order to provide efficient stirring of the melting reactants.
  • suitable solvents include, but are not limited to, benzene, toluene, xylene, mesitylene, chlorobenzene and the like.
  • the ratio of reactants is at least 1:1 : 1 equivalents of urea: compound of Formula I: ammonium salt.
  • a preferred ratio is 3: 1:1 equivalents.
  • the reaction vessel is charged with the reactants and then is purged with nitrogen before heating is begun.
  • ammonia begins to evolve when the reaction mixture reaches a temperature of about 100° or greater.
  • Ammonia can be collected by use of an acid scrubber. Evolution of the ammonia should be monitored and controlled at a reasonable rate by the rate of heating of the reaction mixture.
  • a particularly preferred process of this invention is the preparation of the compound (4R,5S)-l,5-dimethyl-4-phenylimidazolidin-2-one (compound of Formula IIIA).
  • This compound is referred to as the most preferred chiral auxiliary in WO 97/17342 and is a critical intermediate in the stereoselective process disclosed and claimed in WO 97/17342.
  • the entire published application of WO 97/17342 is incorporated by reference into this application.
  • the process is carried out in the presence of the non- volatile ammonium salt at a temperature of 90° to 190°.
  • the reaction is run at the beginning in an inert organic solvent with a boiling point greater than 75°C in order to provide efficient stirring of the melting reactants.
  • suitable solvents include, but not limited to, benzene, toluene, xylene mesitylene, chlorobenzene and the like.
  • the ratio of reactants urea: L- ephedrine:ammonium salt is 3: 1: 1 equivalents.
  • the reaction vessel is purged with nitrogen before heating is begun.
  • ammonia begins to evolve when the reaction mixture reaches a temperature of about 140°.
  • Ammonia can be collected by use of an acid scrubber. Evolution of the ammonia should be monitored and controlled at a reasonable rate by the rate of heating of the reaction mixture.
  • This compound is useful in the preparation of a number of useful pharmaceutical compounds.
  • the reaction vessel was cooled to about 105°C and quenched with 27 L of water. At 57°C, 3 L of ethanol was added. The reaction, as a slurry, was stirred at ambient temperature for 4 hours then was transferred to a basket centrifuge and collected. The centrifuged wet cake was rinsed with 60 L of water and collected to yield 1 1.65 kg of wet cake. The wet cake was dried under vacuum at 20 - 25 °C for 14 hours. The final dry weight of crude product was 10.7 kg (56.25 moles, 65% crude yield). This material was recrystallized from acetonitrile:water (93:7): m.p. 174-175°C; ][ ⁇ ]25 D -96.3° (c 1.0, CH 2 C1 2 ); [ ⁇ ]25/D -46° (c l.O. MeOH).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to the process of making imidazolidine-2-one derivatives comprising the reaction of ephedrine derivatives with urea in the presence of ammonium sulfamate.

Description

PROCESS OF MAKING IMIDAZOLIDINE-2-ONE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to a process to prepare chiral auxiliary intermediates which are useful in the asymmetric syntheses of useful organic compounds. These auxiliaries are imidizolidin-2-ones. Of particular importance, the present invention relates to any improvement in the process to prepare aromatic ring-fused cyclopentane derivatives, specifically indane-2-carboxylates and cyclopentano[b]pyridino-2-carboxylates. This improvement relates to the process for preparing important chiral intermediates used in the preparation of indanes and cyclopentano[b]pyridines. This chiral intermediate is (4R,5S)- l,5-dimethyl-4-phenyl-imidizolidin-2-one.
BACKGROUND OF THE INVENTION
Intermediates that are useful in asymmetric synthesis to produce an asymmetric center are very important to organic chemistry in general and, specifically, within the pharmaceutical field. The term chiral auxiliary means a non-racemic functional group that imparts a distereoselective reaction at a remote prochiral center of a molecule. Chiral auxiliary intermediates which are useful in such synthesis are known in the art. These include l,3-oxazolidin-2-ones, see Soloshonok et al., Org. Letters, 747(2000) and reviews noted therein, and imidiazolidin-2-ones, see Bongini et al., Tetrahedron: Asymmetry, 1996, 1457 and references therein. All information within these references necessary to understand and use this invention are incorporated by reference.
The chiral intermediate (4R,5S)- l,5-dimethyl-4-phenyl-imidizolin-2-one is one of these important auxiliaries useful to prepare pharmaceutically active compounds. Other structurally related iminidazolin-2-ones, including its enantiomer, are also useful. The known literature procedures to make these compounds have a number of problems. An improved method to prepare these auxiliaries was desired. I have now found and disclose useful improvements to the process to prepare these clinical auxiliary intermediates. More specifically, these process improvements can be used to prepare certain endothelin receptor antagonists. Certain indane-2-carboxylic acids and cyclopentano[6]pyridines are useful endothelin receptor antagonists; see U.S. Patent Nos. 5,817,693; 5,716,984 and 5,389,620. The racemates of these compounds have important pharmaceutical activity; however, the enantiomers have improved activity. For example, (+)( 1 S, 1 R,3S)-3-[2-hydroxyeth- 1 -yloxy)-4-methoxyphenyl]- 1 -[3,4-methylenedioxyphenyl)- 5-propoxylindane-2-carboxylic acid and (+)(lS,2R,3S)3-(2-carboxymethoxy-4- methoxyphenyl-l-(3,4-methylene dioxyphenyl)-5-propoxylindane-2-carboxylic acid are under development and are potential commercial products. In a PCT application published on May 15, 1997 under International Publication No. WO 97/17342, an improved process for preparing these enantiomers is described. The imidizolidin-2-one chiral intermediate was disclosed as an important chiral auxiliary intermediate in this process. Synthesis of this intermediate is reported in the literature by condensing urea with ephedrine; see Close, J. Org. Chem., 15, 1131 (1950) and Drewes et al., Chem Ber. 126, 2663 (1993). This literature procedure has several problems associated with it. The yield is lower than is desired for a commercial process. The process also gives an undesirable oxazolidin-2-one impurity as 25-30% of the crude isolated product. Purification is required before the product can be used. In addition, certain by-products, such as ammonium chloride, cyanuric acid and ammonia form solid particulates that tend to block risers in certain fixed vessels and poses a safety hazard. I have found, discovered and disclose in this application an improved process which overcomes the problems associated with the known method.
SUMMARY OF THE INVENTION
The process of this invention involves the following process:
iA Π A wherein:
Ri is Ci .galkyl, cyclohexyl, phenyl, phenyl substituted with Ci .galkyl, halo, nitro, Ci .galkoxy, Ci.galkylmercapto or CF3, napthyl or napthyl substituted with C i.galkyl, halo, nitro, Ci .galkoxy or CF3;
R2 is Ci.galkyl, C i.galkenyl, cyclohexyl, phenyl, or phenylCi .galkyl wherein each phenyl may be substituted with one or two substituents selected from nitro, Ci .galkoxy, methylenedioxy or CF3; and
R3 is C i.galkyl, C i .galkenyl, C3_gcycloalkyl, phenyl or phenylCi .galkyl wherein each phenyl may be substituted with one or two substituents selected from nitro, Ci.galkyl, halo, nitro, Cj.galkoxyl, methylenedioxy, CF3 or dialkylamino, and urea together in the presence of a non- volatile ammonium salt.
The process of this invention proceeds equally with the enantiomer of compound IA (compound IB) to produce the enantiomer of the product IIA (compound LIB). The structures of compounds IB and IIB are as follows: o
I B Π B
wherein Ri , R2 and R3 are as defined above. The chiral auxiliaries defined by compound IIB are also useful in asymmetric synthesis of useful organic compounds.
Within R 1 , a preferred group are those moieties which provide steric bulk such as phenyl, substituted phenyl, napthyl and substituted napthyl. Particularly preferred is phenyl. A wider variety of groups are equally useful in this process within R2 and R3. Preferred R2 and R3 groups are alkyl, phenyl or phenylalkyl. Within Ri , R2 and R3, halo means fluoro, bromo or chloro and alkyl means straight or branched chained alkyl groups.
Compounds of Formula I are commercially available or readily prepared by one skilled in the art by known methods. L-ephedrine, a compound of Formula IA where Ri is phenyl and R2 and R3 are methyl, and D-ephedrine, the related compound of Formula IB, are readily available and cheap compounds which is particularly useful in this process.
The process is carried out in the presence of a non- volatile ammonium salt at a high temperature. Suitable ammonium salts include, but are not limited to, ammonium sulfamate, ammonium sulfate, and ammonium dihydrogen phosphate. Other suitable ammonium salts can be readily determined by one skilled in the art. A preferred ammonium salt is ammonium sulfamate.
The process is run at a temperature of 75°-190°C. The reaction is run in the beginning in an inert organic solvent with a boiling point greater than 75°C in order to provide efficient stirring of the melting reactants. Examples of suitable solvents include, but are not limited to, benzene, toluene, xylene, mesitylene, chlorobenzene and the like. After the reaction is heated to the boiling point of the solvent, it is allowed to distill off. The reaction melt is heated to 160°-190°C until the reaction is completed.
The ratio of reactants is at least 1:1 : 1 equivalents of urea: compound of Formula I: ammonium salt. A preferred ratio is 3: 1:1 equivalents.
The reaction vessel is charged with the reactants and then is purged with nitrogen before heating is begun. During the reaction, ammonia begins to evolve when the reaction mixture reaches a temperature of about 100° or greater. Ammonia can be collected by use of an acid scrubber. Evolution of the ammonia should be monitored and controlled at a reasonable rate by the rate of heating of the reaction mixture.
Work-up of the process by the addition of water results in compound of Formula II in high enantiomeric purity and with minimum amounts of the undesired oxazolidin-2-one impurity. The compound of Formula II can be used directly without additional purification.
A particularly preferred process of this invention is the preparation of the compound (4R,5S)-l,5-dimethyl-4-phenylimidazolidin-2-one (compound of Formula IIIA). This compound is referred to as the most preferred chiral auxiliary in WO 97/17342 and is a critical intermediate in the stereoselective process disclosed and claimed in WO 97/17342. The entire published application of WO 97/17342 is incorporated by reference into this application.
The process to prepare this compound is as follows:
L-ephedrine + urea + NH 3 m A
The process is carried out in the presence of the non- volatile ammonium salt at a temperature of 90° to 190°. The reaction is run at the beginning in an inert organic solvent with a boiling point greater than 75°C in order to provide efficient stirring of the melting reactants. Examples of suitable solvents include, but not limited to, benzene, toluene, xylene mesitylene, chlorobenzene and the like. The ratio of reactants urea: L- ephedrine:ammonium salt is 3: 1: 1 equivalents.
The reaction vessel is purged with nitrogen before heating is begun. During the reaction, ammonia begins to evolve when the reaction mixture reaches a temperature of about 140°. Ammonia can be collected by use of an acid scrubber. Evolution of the ammonia should be monitored and controlled at a reasonable rate by the rate of heating of the reaction mixture.
After the reaction is heated to about 100° or the boiling point of the solvent, the solvent is allowed to distil off and the reaction melt is heated to 160-190°C, preferably 165- 180°C, until the reaction is completed. The most preferred temperature range is 175-179°C. Work-up with water results in compound III in greater than 99.9% enantiomeric purity and an overall yield improvement of 10-25% over published processes. In addition, the oxazolidinone impurity obtained with the older published procedure is produced in less than 1%. Compound III can be used directly as obtained in the process to prepare the desired pharmaceutically important compounds, for example, as used within the process disclosed in WO 97/17432.
The use of D-ephedrine in the particularly preferred process above produces the compound of Formula IIIB.
ΠI B
This compound is useful in the preparation of a number of useful pharmaceutical compounds.
Another advantage of the chiral auxiliaries produced by the process of this invention is that they can be recovered from the asymmetric synthesis and reused. This results in greater economical efficiencies. Without further elaboration, it is believed that one skilled in the art can, using the preceding description and the Examples that follow, utilize the present invention to its fullest extent. The following Examples are to be construed as merely illustrative and not a limitation of the scope of the present invention.
EXAMPLE 1
(4R.5S)- 1 ,5-Dimethyl-4-phenyl-imidazolidin-2-one
To a 20 gallon glass-lined reactor was added toluene (36 L), urea (16.4 kg, 273.3 moles, 3 equiv), ammonium sulfamate (10.35 kg, 92.3 moles, 1 equiv) and L-ephedrine (14.36 kg, 86.9 moles, 1 equiv.). The reaction vessel was purged with nitrogen then was heated to 98°C to remove the toluene. After 40 minutes, all 36 L of toluene was distilled. The reaction was heated to 175°C. Ammonia begins to evolve at ~140°C. After 1.5 hours at 175°C to 180°C, HPLC indicated that the reaction had proceeded to completion. The reaction vessel was cooled to about 105°C and quenched with 27 L of water. At 57°C, 3 L of ethanol was added. The reaction, as a slurry, was stirred at ambient temperature for 4 hours then was transferred to a basket centrifuge and collected. The centrifuged wet cake was rinsed with 60 L of water and collected to yield 1 1.65 kg of wet cake. The wet cake was dried under vacuum at 20 - 25 °C for 14 hours. The final dry weight of crude product was 10.7 kg (56.25 moles, 65% crude yield). This material was recrystallized from acetonitrile:water (93:7): m.p. 174-175°C; ][α]25 D -96.3° (c 1.0, CH2C12); [α]25/D -46° (c l.O. MeOH).
EXAMPLES 2-5
Following the procedures set forth in this specification and of Example 1 , the following chiral auxiliaries are prepared.
IIIA
Example Si E2 S3
2 2,5-dimethoxyphenyl CH3 t-butyl
3 4-hydroxyphenyl CH3 4-hydroxyphenyl-2-ethyl
4 phenyl CH3 3-(3-methoxyphenyl)-3-oxo- propyl
5 4-isopropylmercaptophenyl CH3 n-octyl
EXAMPLE 6 Substituting D-ephedrine for L-ephedrine in the procedure of Example 1 yields the compound (4S,5R)- 1 ,5-dimethyl-4-pheny limidazolidin-2-one.
EXAMPLES 7-10
Following the procedures set forth in this specification and of Example 1 , the following chiral auxiliaries are prepared.
IIIB Example Si S2 S3
7 2,5-dimethoxyphenyl CH3 t-butyl
8 4-hydroxyphenyl CH3 4-hydroxyphenyl-2-ethyl
9 phenyl CH3 3-(3-methoxyphenyl)-3-oxo- propyl
10 4-isopropylmercaptophenyl CH3 n-octyl

Claims

What is claimed is:
1. A process for the preparation of a compound of Formula HA or Formula IIB:
which comprises heating a compound of Formula IA or Formula IB
I A I B
wherein Rj is Ci.galkyl, cyclohexyl, phenyl, phenyl substituted with Ci .galkyl, halo, nitro, C j.galkoxy, Ci.galkylmercapto or CF3, napthyl or napthyl substituted with Ci .galkyl, halo, nitro, C j.galkoxy or CF3;
R2 is Ci.galkyl, Ci.galkenyl cyclohexyl, phenyl, or phenyl Ci.galkyl wherein each phenyl may be substituted with one or two substituents selected from nitro, C j.galkoxy methylenedioxy or CF3; and
R3 is Ci.galkyl, Cj.galkenyl, C3.gcycloalkyl, phenyl or phenyl Ci .galkyl wherein each phenyl may be substituted with one or two substituents selected from nitro, Ci .galkyl, halo, nitro, Ci .galkoxyl, methylenedioxy, CF3 or dialkylamino, and urea together in the presence of a non-volatile ammonium salt.
2. A process of claim 1 wherein Rj is phenyl or substituted phenyl.
3. A process of claim 2 wherein R2 is alkyl.
4. A process of claim 3 wherein R3 is alkyl.
5. A process of claims 1-4 wherein the process is carried out at a temperature of 75-190°C.
6. A process of claim 5 wherein Formula IA is L-ephedrine.
7. A process of claim 6 wherein the process is carried out at 160-190°C.
8. A process for the preparation of (4R,5S)- l,5-dimethyl-4- phenylimidizolidin-2-one which comprises heating about one equivalent L-ephedrine with three equivalents urea and one equivalent ammonium sulfamate at 175-179°C.
9. A process for the preparation of (4S,5R)- 1 ,5-dimethyl-4-phenyl- imidizolidin-2-one which comprises heating about one equivalent D-ephedrine with three equivalents urea and one equivalent ammonium sulfamate at 165-180°C.
10. The compound (4R,5S)- 1 ,5-dimethyl-4-phenylimidizolidine-2-one or (4S,5R)-l,5-dimethyl-4-phenylimidizolidin-2-one when prepared by the process of claims
EP00947137A 1999-07-09 2000-07-07 Process of making imidazolidine-2-one derivatives Withdrawn EP1210334A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14311099P 1999-07-09 1999-07-09
US143110P 1999-07-09
PCT/US2000/018691 WO2001004098A1 (en) 1999-07-09 2000-07-07 Process of making imidazolidine-2-one derivatives

Publications (2)

Publication Number Publication Date
EP1210334A1 true EP1210334A1 (en) 2002-06-05
EP1210334A4 EP1210334A4 (en) 2002-09-25

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EP00947137A Withdrawn EP1210334A4 (en) 1999-07-09 2000-07-07 Process of making imidazolidine-2-one derivatives

Country Status (7)

Country Link
EP (1) EP1210334A4 (en)
JP (1) JP2003504357A (en)
AR (1) AR035555A1 (en)
AU (1) AU6079600A (en)
CO (1) CO5200764A1 (en)
HK (1) HK1046907A1 (en)
WO (1) WO2001004098A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10215845A1 (en) * 2002-04-11 2003-10-23 Basf Ag Process for the preparation of chiral imidazolidin-2-ones

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MELNYK, O. ET AL: "Additions Diastéréosélectives d'Alkyl, Alcényl et Allyl Cuprates à des Imides Chirales Insaturées" TETRAHEDRON, vol. 48, no. 5, 1992, pages 841-850, XP002207097 *
See also references of WO0104098A1 *

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HK1046907A1 (en) 2003-01-30
AU6079600A (en) 2001-01-30
JP2003504357A (en) 2003-02-04
EP1210334A4 (en) 2002-09-25
AR035555A1 (en) 2004-06-16
WO2001004098A1 (en) 2001-01-18
CO5200764A1 (en) 2002-09-27

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