MXPA06005255A

MXPA06005255A - Processes for the preparation of n-substituted phthalimides

Info

Publication number: MXPA06005255A
Application number: MXPA/A/2006/005255A
Authority: MX
Inventors: Wu Yanzhong; Raveendranath Panolil
Original assignee: Wyeth
Priority date: 2003-11-17
Filing date: 2006-05-10
Publication date: 2006-10-17

Abstract

The present invention describes a process for preparing N-substituted phthalimides of Formula:(I) which are widely useful as intermediates in the preparation of organic compounds such as pharmaceuticals.

Description

PROCESS FOR THE PREPARATION OF N-SUBSTITUTE FTALIMIDES FIELD OF THE INVENTION The present invention relates to processes for the preparation of N-substituted phthalimides. BACKGROUND OF THE INVENTION N-substituted phthalimides are useful intermediates for the synthesis of a large variety of primary amines by means of well-known processes, such as the Gabriel synthesis (e.g., Gibson et al., Angew. Chem. Int. Ed.

Engl. , 1968, 7, 919) and the Manske procedure (Ing et al., J. Chem. Soc., 1926, 2348). The N-substitution of phthalimides can be mediated by the versatile Mitsunobu reaction (Mitsunobu et al., Bull. Chem. Soc. Jpn., 1961, 40, 2380; Camp et al., Aust. J. Chem. 1988, 41, 1835), the general representation of which is shown below in Reaction Scheme I. This reaction usually uses a triarylphosphine and a dialkyl azodicarboxylate as the reactants, which serve to activate a primary or secondary alcohol towards nucleophilic attack by acidic or weakly acidic groups, such as phenols, carboxylic acids, diamides, etc. While the Mitsunobu reaction is a versatile synthesis tool, since it allows it to activate and directly replace an alcohol group in one stage, it has the disadvantage of generating REF. : 172765 the undesirable byproducts of triphenylphosphine oxide and a dialkyl, diacyl hydrazide in stoichiometric amounts. These reaction by-products, in addition to any of the unreacted reactants can often lead to difficult or tedious separations, thus potentially limiting the industrial utility of the process.

Reaction Scheme I As can be appreciated well by the skilled person, N-substituted phthalimides are widely useful in all areas of synthetic chemistry and particularly in pharmaceutical research. For example, 2- (3-butynyl) -1-H-isoindol-l, 3- (2H) -dione is used in the preparation of pain relieving drugs that are inhibitors of the cytosolic phospholipase A2 enzyme as reported in, for example, WO 03/048122A2. Preparations of this intermediate through the Mitsunobu reactions and other reactions have also been reported in Griffiths et al., Tetzahedzon, 1992, 48, 5543; Jackson et al., Aust. J. Chem., 1988, 41, 1201; Minutes Pharm. Suec. , 1975, 12, 290; Jackson et al., Tetrahedron, 1988, 29, 1983; Hoffmann et al., J. Med. Chem. , 1975, 18, 278; NL 6600916; NL 6501131; and lyer et al., J. Am. Chem. Soc., 1987, 109, 2759. These preparations, however, tend to involve multistage synthesis, initiating materials not available commercially, long reaction times, chlorinated solvents and / or complicated isolation or purification steps. Therefore, improved synthesis routes are needed for the N-substituted phthalimides and the processes described herein that help meet these and other needs. BRIEF DESCRIPTION OF THE INVENTION The present invention provides a process for preparing a compound of formula I: wherein: R is hydrogen, C? _2 alkyl, halogen or C1-2 alkoxy; Ri is hydrogen, C6-6 alkyl, C2-6 alkenyl or c2-e alkynyl; and R 2 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; which comprises reacting a compound of formula II: with a compound of formula III: H OH 111 in the presence of a diazodicarboxylate having the formula IV: IV wherein each R3 is, independently, C? _6 alkyl; and in the presence of a triarylphosphine of the formula V: P (Ar) 3 V wherein each Ar is phenyl optionally substituted with 1-3 substituents independently selected from CH 3, OCH 3 and halogen; and in the presence of a solvent having the formula VI: Ar 'VI wherein Ar 'is phenyl optionally substituted with 1, 2 or 3 methyl groups; for a time and under appropriate conditions to form the compound of Formula I. In some embodiments, R is hydrogen, alkyl Ca_2, halogen or C2-2 alkoxy; i is hydrogen; and R 2 is C 1 -C alkyl, C 2 al alkenyl or C 2-6 alkynyl. In further embodiments, R is hydrogen, C? _2 alkyl, halogen or C? _2 alkoxy; Rx is hydrogen; and R2 is C2_6 alkenyl or C2_6 alkynyl. In further embodiments, R is hydrogen; Rx is hydrogen and R2 is C2-6 alkenyl or C2_6 alkynyl. In still further embodiments, R is hydrogen; i is hydrogen and R2 is propynyl. In some embodiments, the compound of Formula I has the formula: According to some embodiments, the triarylphosphine of formula V is triphenylphosphine. According to further embodiments, R3 is methyl, ethyl, propyl, for example 2-propyl. According to further embodiments, the solvent of formula VI is toluene. In still further embodiments, the diazodicarboxylate of formula IV is added to a mixture of compounds of Formulas II, III, V and VI. The mixture can be maintained at a temperature of about -10 to about 30 ° C, and in some embodiments of about -10 to about 10 ° C, during the addition. In some embodiments, the diazodicarboxylate of Formula IV is added to a mixture of compounds of Formulas II, III, V and VI at a rate, so that the reaction temperature is maintained at or below room temperature. In some embodiments, the processes described herein include precipitating the compound of Formula I from the reaction mixture, which can be induced by the addition of alcohol to the reaction mixture. These alcohols may include alkanols having 1-10 carbon atoms, for example, methanol, ethanol, C3 alkanol, C4 alkanol, C5 alkanol, C6 alkanol, C7 alkanol, C8 alkanol, C9 alkanol, C ?0 alkanol, or combinations thereof. same. In some embodiments, the alcohol comprises methanol. Preferably, the volume ratio of the alcohol to the solvent is from about 1: 1 to about 1: 2. According to some embodiments, the compound of formula I is isolated by filtration and has a purity greater than about 95%. Preferably, the compound of Formula I is isolated by filtration in a yield greater than about 70% by weight based on the amount of compound of Formula II. In still further embodiments, the compound of the formula I is isolated by filtration in a yield greater than about 70% by weight based on the amount of the compound of the Formula II and with a purity greater than about 95% without the use of distillation, extraction or additional chromatography. DETAILED DESCRIPTION OF THE INVENTION The present invention provides, inter alia, processes for preparing N-substituted phthalimides starting with primary or secondary alcohols. The processes described herein allow the isolation of substantially pure N-substituted phthalimides without the use of. purification methods by distillation or chromatography. A general representation of the processes of the present invention is provided in the Reaction Scheme II, wherein the constituent elements of the compounds represented in Formulas I, II, III, IV, V and VI are defined above.

Reaction Scheme II The preparation of the N-substituted phthalimides according to the processes of the present invention, for example, can be carried out by combining in a single vessel the compounds of Formulas I, III, IV, V and VI. In general, the diazodicarboxylate of Formula IV is the final component to be added, so that the diazodicarboxylate is added to the mixture of compounds of Formulas II, III, V and VI. The addition can be carried out at reduced temperature. For example, the mixture of compounds of Formulas II, III, V and VI can be cooled before the addition of diazodicarboxylate. Suitable temperatures at which the mixture can be cooled include about -20 to about 15 ° C, preferably about -10 to about 10 ° C, and more preferably from about 0 to about 5 ° C. The addition of the diazodicarboxylate can result in an exothermic reaction and heating of the reaction mixture. The rate of addition can be regulated so that the temperature of the reaction mixture does not rise above a certain threshold temperature, such as about room temperature. For example, the rate of addition can be controlled so that the temperature of the reaction mixture is maintained from about 0 to about 30 ° C., preferably from about 10 to about 25 ° C or more preferably from about 15 to about 25 ° C. After the addition of the diazodicarboxylate, the reaction can be carried out for an additional amount of time until it is complete. For example, the reaction mixture may be stirred for an additional 30 to 90 minutes or approximately 60 minutes, at any suitable temperature, such as 10 to about 30 ° C, 15 to about 25 ° C or about room temperature.

The isolation of the compound of formula I from the reaction mixture can be carried out without the use of distillation, extraction or chromatographic techniques. For example, the compound of the formula I can be precipitated directly in a good yield and purity of the reaction mixture. The precipitation can be induced by the addition of an adequate amount of solvent in which the compound of the formula I is poorly soluble. For example, the addition of a sufficient amount of an alcohol can induce precipitation to allow the reaction by-products to remain in solution for ease of separation. Suitable alcohols include methanol, ethanol, n-propanol, isopropanol, t-butanol, and the like. A combination of alcohols can also be used. Yields, by weight, greater than about 50%, about 60%, about 70% and about 80% can be obtained in this manner, and a purity greater than about 80%, about 85%, about 90%, about 95%, can be obtained. %, approximately 98% and approximately 99% without the additional purification steps. The processes of the present invention are advantageous for numerous obvious reasons for experienced persons. For example, developing the reaction in an aromatic solvent (Ar ') and the subsequent addition of alcohol results in precipitation of the product from the reaction mixture while allowing undesired byproducts and excess reagents to remain in solution, facilitating this way the purification. In addition, the use of common halogenated Mitsunobu solvents, such as methylene chloride or chloroform, which may present residual treatment difficulties, or the use of some ether solvents that can form potentially harmful organic peroxides, is avoided. As used herein, the term "Alkyl" or "Alkylene" is understood to refer to a saturated hydrocarbon group that is straight or branched chain.

Examples of the alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and Similar . An alkyl group may contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Examples of the alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl and the like. As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Examples of the alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like. As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. As used herein, "alkoxy" refers to an -O-alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy and the like. As used herein, the term "react" refers to combining the designated chemical reagents, so that a chemical transformation is carried out that generates a compound different from any initially introduced into the system. The reaction is carried out in the presence or absence of solvent. At different sites in the present specification, the substituents of the compounds of the invention are described in groups or in ranges. It is specifically intended that the invention include each and any sub-combination of the elements of such groups and ranges. For example, the term "C?-6 alkyl" is specifically intended to individually describe methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, Cs alkyl.

The compounds of the present invention may contain an asymmetric atom, and some of the compounds may contain one or more asymmetric atoms or centers, which, in this way, can give rise to the optical isomers (enantiomers) and diastereomers. The present invention includes these optical isomers (enantiomers) and diastereomers (geometric isomers); as well as the resolved R and S stereoisomers, enantiomerically pure; as well as other mixtures of the stereoisomers R and S and the pharmaceutically acceptable salts thereof. The optical isomers can be obtained in the pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diastereomeric salt formation, kinetic resolution and asymmetric synthesis. It is also understood that this invention encompasses all possible regioisomers and mixtures thereof, which can be obtained in the pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography. , thin layer chromatography, and high performance liquid chromatography. The processes described herein can be monitored according to the appropriate method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., visible UV) or mass spectrometry or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography. The reactions of the processes described herein can be carried out in appropriate solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the initiator materials (reactants), intermediates, or products at the temperatures at which the reactions are carried out, for example, temperatures that may range from the freezing temperature of the solvent to the boiling temperature of the solvent. Solvents which are suitable according to the present invention are the solvents of Formula VI which include benzene and toluene. The reactions of the processes described herein can be carried out at the appropriate temperatures, which can be easily determined by the experienced person. The reaction temperatures will depend, for example, on the melting and boiling points of the reactants and the solvent, if present; the thermodynamics of the reaction (for example, vigorously exothermic reactions are usually carried out at reduced temperatures); and the kinetics of the reaction (for example, a high activation energy barrier usually needs high temperatures). "High temperatures" refers to temperatures above room temperature (approximately 20 ° C) and "reduced temperature" refers to temperatures below room temperature. The reactions of the processes described herein may be carried out in air or under an inert atmosphere. In general, reactions containing reagents or products that are substantially reactive with air can be carried out using air sensitive synthesis techniques that are well known to those skilled in the art. It is appreciated that some characteristics of the invention, which are, for clarity, described in the context of the separate embodiments, may also be provided in combination in a single embodiment. On the contrary, several of the features of the invention which, for clarity, are described in the context of a single embodiment, may also be provided separately or in any appropriate sub-combination. The processes of this invention are suitable for the preparation of the compounds of the formula I at any convenient scale, for example greater than about 0.01 mg, 0.10 mg, 1 mg, 10 mg, 100 mg, 1 g, 10 g, 100 g, 1 kg, 10 kg or more. The processes are particularly advantageous for the large-scale preparation (eg, greater than about ten grams) of the compounds of the formula I. The invention will be described in greater detail in the manner of the specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially the same results.

EXAMPLE PREPARATION OF 2-BUT-3-INIL-ISOINDOL-1, 3-DIONA Diisopropyl azodicarboxylate (316 g, 1.56 mol) was added to a solution of triphenylphosphine (PPh3) (393 g, 1.50 mol), 3-butyn-1-ol (105 g, 1.50 mol) and phthalimide (200 g, 1.36 mol). ) in toluene (1600 mL) which was pre-cooled with a cooling bath at -5 ° C, at the rate that the temperature of the reaction mixture was maintained between 15-25 ° C. The addition time was 50 minutes. The cooling bath was removed after the addition was complete. The reaction mixture was allowed to warm to 15-25 ° C and was stirred for 1 h. Then methanol (800 mL) was added. The mixture was stirred for 30 minutes and then filtered. The crude product was washed with methanol and dried to give a white solid (218 g) in a yield of 81% and 99.8% purity per area. "" "H NMR (DMSO-d6): d 7.88 (m, 4H), 3.72 (t, 2H, J = 7.0 Hz), 2.83 (t, 1H, J = 2.7 Hz), 2.55 (m, 2H). As those skilled in the art will appreciate, numerous changes and modifications may be made to the preferred embodiments of the invention without departing from the spirit and scope of the invention, It is intended that these variations fall within the scope of the invention. the patents, applications and printed publications including the books mentioned in this patent document are hereby incorporated by reference in their entirety This application claims the benefit of the priority of the provisional US application Serial No. 60 / 520,757 filed on 17 November 2003, which is hereby incorporated by reference in its entirety It is noted that with respect to this date, the best method known to the applicant to carry out said invention is that which is clear from the present description n of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is cla as property: 1. A process for preparing a compound of the formula I: characterized in that: R is hydrogen, C? _2 alkyl, halogen or C? _2 alkoxy; Ri is hydrogen, C6-6 alkyl, C2_6 alkenyl or C2-6 alkynyl; and R2 is C6_6 alkyl, C2_6 alkenyl or C2_6 alkynyl; which comprises reacting a compound of formula II: wherein R is as defined above, with a compound of formula III:
H OH Ri R2 111 wherein Ri and R2 are as defined above, in the presence of a diazodicarboxylate having the formula IV:
IV wherein each R3 is, independently, C? _6 alkyl; and in the presence of a triarylphosphine of the formula V:
P (Ar) 3 V wherein each Ar is phenyl optionally substituted with 1-3 substituents independently selected from CH 3, OCH 3 and halogen; and in the presence of a solvent having the formula VI:
Ar 'VI wherein Ar 'is phenyl optionally substituted with 1, 2 or 3 methyl groups; to form the compound of Formula I. 2. A process according to claim 1, characterized in that Ri is hydrogen. 3. A process according to claim 1 or claim 2, characterized in that R2 is C2_6 alkenyl or C2-6 alkynyl. 4. A process according to claim 3, characterized in that R2 is propinyl. 5. A process according to any of claims 1 to 4, characterized in that R is hydrogen.
6. A process according to claim 1, characterized in that the compound of Formula I has the formula:
7. A process according to any of claims 1 to 6, characterized in that the triarylphosphine of the formula V is triphenylphosphine.
8. A process according to any of claims 1 to 7, characterized in that R3 is independently selected from the group consisting of methyl, ethyl, n-propyl and 2-propyl.
9. A process according to any of claims 1 to 7, characterized in that each R3 is n-propyl.
10. A process according to any of claims 1 to 7, characterized in that each R3 is 2-propyl.
11. A process according to any of claims 1 to 10, characterized in that the solvent of Formula IV is toluene.
12. A process according to any of claims 1 to 11, characterized in that the diazodicarboxylate of the formula IV is added to a mixture of compounds of the formulas II, III, V and VI.
13. A process according to claim 12, characterized in that the diazodicarboxylate of Formula IV is added to the mixture of the compounds of Formulas II, III, V and VI at a rate such that the reaction temperature is maintained at about -10 ° C to about 30 ° C. A process according to claim 13, characterized in that the mixture is maintained at a temperature of about -10 ° C to about 10 ° C throughout the entire duration of the addition of diazodicarboxylate. 15. A process according to any of claims 1 to 14, characterized in that it further comprises precipitating the compound of the formula I from the reaction mixture. 16. A process according to claim 15, characterized in that the precipitation is induced by the addition of alcohol to the reaction mixture formed from this reaction. 17. A process according to claim 16, characterized in that the alcohol comprises methanol, ethanol, isopropanol or a combination thereof. 18. A process according to claim 16, characterized in that the alcohol comprises methanol. 19. A process according to any of claims 16 to 18, characterized in that the volume ratio of the alcohol to the solvent is from about 1: 1 to about 1: 2. 20. A process according to any of claims 15 to 19, characterized in that the compound of formula I is isolated by filtration and the isolated compound has a purity greater than about 95%. 21. A process according to any of claims 15 to 19, characterized in that the compound of the formula I is isolated by filtration in a yield greater than about 70% by weight based on the amount of the compound of the formula II. 22. A process according to any of claims 15 to 19, characterized in that the compound of the formula I is isolated by filtration in a yield greater than about 70% by weight based on the compound of the formula II and with a higher purity of approximately 95% without the use of additional distillation, extraction or chromatographic techniques. 23. A process according to claim 14, characterized in that it further comprises precipitating the compound of the formula I from the reaction mixture by the addition of an alcohol, wherein the volume ratio of the alcohol to the solvent is about 1: 1. to about 1: 2. 24. A process according to claim 23, characterized in that: the alcohol comprises methanol, ethanol, isopropanol or a combination thereof; the solvent is toluene; R is hydrogen; Rx is hydrogen; R2 is propinyl; each R3 is 2-propyl and each Ar is phenyl.