JP2003504357A - Method for producing imidazolidine-2-one derivative - Google Patents

Abstract

  (57) [Summary] The present invention relates to a method for producing an imidazolidine-2-one derivative comprising a reaction between an ephedrine derivative and urea in the presence of ammonium sulfamate.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to methods for preparing chiral auxiliary intermediates useful in the asymmetric synthesis of useful organic compounds. These auxiliaries are the imidazolidin-2-ones. Of particular importance, the present invention provides cyclopentane derivatives fused with aromatic rings,
In particular, indan-2-carboxylate and cyclopentano [b] pyridino-
It relates to any improvement in the production of 2-carboxylates. The improvements relate to the preparation of key chiral intermediates used in the preparation of indane and cyclopentano [b] pyridines. The chiral intermediate is (4R, 5S) -1,5-dimethyl-4-phenyl-imidazolidin-2-one.

BACKGROUND OF THE INVENTION Intermediates useful in asymmetric synthesis to form asymmetric centers are of great importance to organic chemistry in general, and particularly within the pharmaceutical field. The term chiral auxiliary is
By non-racemic functional group which provides a diastereoselective reaction at remote prochiral centers of the molecule. Chiral auxiliary intermediates useful in such syntheses are known in the art. These are 1,3-oxazolidin-2-ones (Soloshonok et al., Org. Let.
ters, 747 (2000) and review therein) and imidazolidine-2-
Ons (see Bongini et al., Tetrahedron: Asymmetry, 1996, 1457 and references cited therein). All information in these references that is necessary for understanding and using the invention is incorporated herein by reference.

The chiral intermediate (4R, 5S) -1,5-dimethyl-4-phenyl-imidazolidin-2-one is one of these important auxiliaries useful in preparing pharmaceutically active compounds. Is one. Other structurally related imidazolidin-2-ones, including their enantiomers, are also useful. Known literature techniques for making these compounds have several problems. Improved methods for preparing these auxiliaries were desired. The inventors have now found and disclosed useful improvements to the process for making these chiral auxiliary intermediates.

More particularly, these process improvements can be used to prepare certain endothelin receptor antagonists. Certain indan-2-carboxylic acids and cyclopentano [b] pyridines are useful endothelin receptor antagonists (US 5817693; 5716984 and 5389).
620). Racemates of these compounds have important pharmaceutical activity; enantiomers have improved activity. For example, (+) (1S, 1R, 3
S) -3- [2-Hydroxyeth-1-yloxy) -4-methoxyphenyl]
-1- [3,4-methylenedioxyphenyl) -5-propoxylindan-2
-Carboxylic acid and (+) (1S, 2R, 3S) 3- (2-Carboxymethoxy-4-methoxyphenyl-1- (3,4-methylenedioxyphenyl) -5-propoxylindan-2-carboxylic acid Is a product under development and potential.

In the PCT application published May 15, 1997 under International Publication No. WO 97/17342, improved methods for preparing these enantiomers are described. The imidazolidin-2-one chiral intermediate was disclosed as a key chiral auxiliary intermediate in the process. Synthesis of the intermediate by condensation of urea with ephedrine has been reported in the literature (Cl
ose, J. Org. Chem., 15, 1131 (1950) and Drewes et al., Chem. Ber. 126, 2663.
(1993)). The method of that document has some problems associated with it. Yields are lower than desired for commercial processes. The process also yields undesired oxazolidin-2-one contaminants as 25-30% of the crude isolated product. Purification is required before use of the product. In addition, certain by-products such as ammonium chloride, cyanuric acid and ammonia form solid particles that tend to block the riser in certain fixed vessels, presenting a safety hazard. The inventor has found, acknowledged and disclosed in this application improved methods that overcome the problems associated with known methods.

[0006] (Disclosure of the invention)   The invention is:

[Chemical 3] [In the formula:   R₁Is C_1-8Alkyl, cyclohexyl, phenyl, C_1-6Alkyl,
Halo, nitro, C_1-6Alkoxy, C_1-6Alkyl mercapto or CF_Three Phenyl, naphthyl or C substituted with_1-6Alkyl, halo, nitro, C _1-6 Alkoxy or CF_ThreeNaphthyl substituted with   R_TwoIs C_1-8Alkyl, C_1-8Alkenyl, cyclohexyl, phenyl
, Or phenyl C_1-6Alkyl, where each phenyl is nitro, C _1-6 Alkoxy, methylenedioxy or CF_Three1 or 2 selected from
Optionally substituted with a substituent of   R_ThreeIs C_1-12Alkyl, C_1-8Alkenyl, C_3-6Cycloalkyl
, Phenyl or phenyl C_1-6Alkyl, where each phenyl is
Toro, C_1-6Alkyl, halo, nitro, C_1-6Alkoxy, methylene dioxy
CF_ThreeOr substituted with 1 or 2 substituents selected from dialkylamino
May have been done] Including the steps shown in.

The process of the present invention proceeds equally with the enantiomer of compound IA (compound IB) to yield the enantiomer of product IIA (compound IIB). Compound I
The structures of B and IIB are as follows:

[Chemical 4] [Wherein R ₁ , R ₂ and R ₃ are as described above]. Chiral auxiliaries defined by compound IIB are also useful in the asymmetric synthesis of useful organic compounds.

Preferred groups of R ₁ are moieties that provide steric bulk, such as phenyl, substituted phenyl, naphthyl and substituted naphthyl. Phenyl is particularly preferable. A wider variety of groups is equally useful in the method at R ₂ and R ₃ . Preferred R ₂ and R ₃ groups are alkyl, phenyl or phenylalkyl. In R ₁ , R ₂ and R ₃ , halo means fluoro, bromo or chloro, and alkyl means a straight chain or molecular chain alkyl group. Compounds of formula I are either commercially available or readily prepared by those skilled in the art by known methods. L-ephedrine, a compound of formula IA (wherein R ₁ is phenyl and R ₂ and R ₃ are methyl), and D-ephedrine, a related compound of formula IB, are readily available, It is an inexpensive compound that is particularly useful in the method.

The method is carried out at elevated temperature in the presence of non-volatile ammonium salts. 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 of ordinary skill in the art. A preferred ammonium salt is ammonium sulfamate. The method is carried out at 75-190 ° C. In order to provide effective stirring of the molten reactants, the reaction is first carried out in an inert organic solvent having a boiling point above 75 ° C. Examples of suitable solvents include, but are not limited to, benzene, toluene, xylene, mesitylene, chlorobenzene and the like. The reaction is heated to the boiling point of the solvent and then distilled off. The reaction melt is 160-1 until the reaction is complete.
Heat to 90 ° C. The reactant ratio is at least 1: 1: 1 equivalents of urea: compound of formula I: ammonium salt. The preferred ratio is 3: 1: 1 equivalent.

The reaction vessel is filled with the reactants and then purged with nitrogen before heating is begun. During the reaction, ammonia begins to evolve when the reaction mixture reaches a temperature of about 100 ° C. or higher. Ammonia can be collected by using an acid scrubber. Ammonia evolution should be monitored and regulated at a reasonable rate depending on the heating rate of the reaction mixture. Work-up of the process by addition of water yields the compound of formula II at high enantiomeric purity with a minimal amount of undesired oxazolidin-2-one contaminants. The compound of formula II can be used directly without further purification.

A particularly preferred method of the present invention is the compound (4R, 5S) -1,5-dimethyl-4
-Preparation of phenylimidazolidin-2-one (compound of formula IIIA). The compounds are key intermediates in the stereoselective processes mentioned in WO 97/17342 and disclosed and claimed in WO 97/17342 as the most preferred chiral auxiliaries. The entire published application of WO 97/17342 is
It is made a part of this application by clarification of the source.

[0012]   The method for preparing the compound is as follows:

[Chemical 5]

The method is carried out at 90-190 ° C. in the presence of non-volatile ammonium salts. To provide effective stirring of the molten reactants, the reaction is first conducted at 75 ° C.
It is carried out in an inert organic solvent having a higher boiling point. Examples of suitable solvents include, but are not limited to, benzene, toluene, xylene, mesitylene, chlorobenzene and the like. Ratio of reactants, urea: L-ephedrine: ammonium salt is 3:
1: 1 equivalent. The reaction vessel is purged with nitrogen before heating begins. During the reaction, ammonia begins to evolve when the reaction mixture reaches about 140 ° C. Ammonia can be collected by using an acid scrubber. Ammonia evolution should be monitored and regulated at a reasonable rate depending on the heating rate of the reaction mixture.

After heating the reaction to about 100 ° C. or the boiling point of the solvent, the solvent is distilled off and the reaction melt is heated to 160-190 ° C., preferably 165-180 ° C. until the reaction is complete. The most preferable temperature range is 175 to 179 ° C. Work-up with water yields compound III with enantiomeric purity above 99.9% and overall yield improvement of 10-25% over published methods.
Furthermore, oxazolidinone contaminants obtained by the previously published procedure are produced at less than 1%.

Compound III can be used directly as obtained in the process for preparing the desired pharmaceutically important compound, eg as used within the process disclosed in WO 97/17342. Use of D-ephedrine in the above particularly preferred method produces compounds of formula IIB.

[0016]

[Chemical 6]

The compounds are useful in the preparation of some useful pharmaceutical compounds. Another advantage of the chiral auxiliaries produced by the process of the invention is that they can be recovered from asymmetric synthesis and reused. This results in greater economic efficiency. Without further elaboration, it is believed that those skilled in the art can utilize the invention to its full scope, using the above description and the examples below. The following examples are to be construed as merely illustrative and not limiting the scope of the invention.

Example 1 (4R, 5S) -1,5-Dimethyl-4-phenyl-imidazolidin-2-one In a 20 gallon glass lined reactor, toluene (36 L), urea (16.4 k).
g, 273.3 mol, 3 equivalents), ammonium sulfamate (10.35 kg)
, 92.3 mol, 1 eq) and L-ephedrine (14.36 kg, 86.9).
Mol, 1 eq) was added. The reaction vessel was purged with nitrogen and then heated to 98 ° C. to remove toluene. After 40 minutes, a total of 36 L of toluene had distilled. The reaction was heated to 175 ° C. At ~ 140 ° C ammonia begins to evolve. 175 ° C-18
After 1.5 hours at 0 ° C., HPLC showed the reaction was going to completion. The reaction vessel was cooled to about 105 ° C. and quenched with 27 L water. At 57 ° C, 3 L of ethanol was added. The reaction was slurried and stirred at ambient temperature for 4 hours, then
Transferred to a basket centrifuge and collected. The centrifuge wet cake was rinsed with 60 L of water and collected to obtain 11.65 kg of wet cake. The wet cake was dried under vacuum at 20-25 ° C. for 14 hours. The final dry weight of the crude product is
It was 10.7 kg (56.25 mol, 65% crude yield). The material was recrystallized from acetonitrile: water (93: 7). mp 174-175 ° C; [α] 25 / D -96.3 ° (c 1.0, CH ₂ C1 ₂ ); [α] 25 / D -46 ° (c 1.0, M
eOH)

Examples 2-5 The following chiral auxiliaries are prepared according to the procedure provided herein and in Example 1.

[0020]

[Chemical 7] Example R ₁ R ₂ R ₃ 2 2,5-dimethoxyphenyl CH ₃ t-butyl 3 4-human ethoxyphenyl CH ₃ 4-human oxyphenyl-2-ethyl 4 phenyl CH ₃ 3- (3-methoxyphenyl) -3- Oxo-propyl-5-isopropylmercaptophenyl CH ₃ n-octyl

Example 6 The compound (4S, 5R) -1,5-dimethyl-4-phenylimidazolidin-2-one is obtained by using D-ephedrine instead of L-ephedrine in the procedure of Example 1. .

Examples 7-10 The following chiral auxiliaries are prepared according to the procedure provided herein and in Example 1.

[0023]

[Chemical 8] Example R ₁ R ₂ R ₃ 7 2,5-dimethoxyphenyl CH ₃ t-butyl 8 4-human oxyphenylphenyl CH ₃ 4-human oxyphenyl-2-ethyl 9 phenyl CH ₃ 3- (3-methoxyphenyl) -3- Oxo-propyl 10 4 -isopropyl mercaptophenyl CH ₃ n-octyl

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AU, BA, BB, BG, BR, CA, CN, CZ, DZ, EE, GE, G H, GM, HR, HU, ID, IL, IN, IS, JP , KP, KR, LC, LK, LR, LT, LV, MA, MG, MK, MN, MX, MZ, NO, NZ, PL, R O, SG, SI, SK, SL, TR, TT, TZ, UA , US, UZ, VN, YU, ZA

Claims (10)

[Claims] 1. Formula IA or formula IB: [In the formula, R ₁ is C _1-8 alkyl, cyclohexyl, phenyl, C _1-6 alkyl, halo, nitro, C _1-6 alkoxy, C _1-6 alkylmercapto or CF ₃ -substituted phenyl, naphthyl. Or naphthyl substituted with C _1-6 alkyl, halo, nitro, C _1-6 alkoxy or CF ₃ ; R ₂ is C _1-8 alkyl, C _1-8 alkenylcyclohexyl, phenyl,
Or phenyl C _1-6 alkyl, wherein each phenyl is nitro, C _{1 -6} alkoxy, may be substituted with 1 or 2 substituents selected from methylenedioxy or CF _3; R ₃ is C _1-12 alkyl, C _1-8 alkenyl, C _3-6 cycloalkyl, phenyl or phenyl C _1-6 alkyl, wherein each phenyl is nitro, C _1-6 alkyl, halo. , Nitro, C _1-6 alkoxy, methylenedioxy, CF ₃ or dialkylamino may be substituted with one or two substituents] and the presence of a nonvolatile ammonium salt Formula IIA or Formula IIB, characterized in that they are heated together under: The manufacturing method of the compound shown by. 2. The process according to claim 1, wherein R ₁ is phenyl or substituted phenyl. 3. The method according to claim 2, wherein R ₂ is alkyl. 4. The method according to claim 3, wherein R ₃ is alkyl. 5. The method according to claim 1, which is carried out at 75 to 190 ° C. 6. The process according to claim 5, wherein formula IA is L-ephedrine. 7. The production method according to claim 6, which is carried out at 160 to 190 ° C. 8. A (4R, 5S) -1,5-dimethyl characterized in that about 1 equivalent of L-ephedrine is heated at 175-179 ° C. with 3 equivalents of urea and 1 equivalent of ammonium sulfamate. Method for producing -4-phenylimidazolidin-2-one. 9. About 4 equivalents of D-ephedrine are heated at 165-180 ° C. with 3 equivalents of urea and 1 equivalent of ammonium sulfamate at (4S, 5R) -1,5-dimethyl. -4-Phenyl-imidazolidine-2-
On manufacturing method. 10. A compound (4R, 5S) -1,5-dimethyl-4-phenylimidazolidine-2 prepared by the method according to any one of claims 1 to 9.
-One or (4S, 5R) -1,5-dimethyl-4-phenylimidazolidin-2-one.