HK1168851B - Method for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione compounds - Google Patents

Abstract

The present invention provides new methods for preparing unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds, which are useful, for example, for the prevention or treatment of diseases or conditions relating to an abnormally high level or activity of TNF-α. The invention also provides improved and/or efficient methods for commercial production of unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione compounds, including, but not limited to, unsubstituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

Description

Process for preparing 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compounds

The patent application of the invention is a divisional application of an invention patent application with the international application number of PCT/US2006/026210, the international application date of 29.6.2006 and the application number of 200680031945.3 in China national phase, and the name of the invention patent application is '4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compound preparation method'.

1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional application No. 60/696,224 filed on 30/6/2005.

2. Field of the invention

The present invention provides methods for preparing compounds useful for reducing the level or activity of tumor necrosis factor alpha in a mammal. More specifically, the present invention provides a process for the preparation of unsubstituted and substituted 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compounds.

3. Background of the invention

Excessive or unregulated production of tumor necrosis factor alpha or TNF-alpha is implicated in a number of disease conditions. These include endotoxemia and/or toxic shock syndrome (Tracey et al, Nature330, 662-664(1987) and Hinshaw et al, circle. shock 30, 279-292(1990)), cachexia (Dezube et al, Lancet 335(8690), 662(1990)) and adult respiratory distress syndrome (Millar et al, Lancet 2(8665), 712-714 (1989)). Certain substituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolines have been shown in the literature to reduce TNF- α levels, as described in International publication No. WO 98/03502 and Muller et al, bioorg. Med. chem. Lett.9, 1625-1630 (1999).

Substituted isoindole-1, 3-diones which have proven to be of therapeutic value are 2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-diones (THALOMIDs)^TM). It has been demonstrated or believed that the compounds may be useful in the treatment or prevention of a variety of diseases and conditions, including but not limited to inflammation, autoimmune diseases, cancer, heart disease, genetic diseases, allergy, osteoporosis, and lupus.

U.S. Pat. Nos. 6,395,754 and 5,635,517 disclose prior methods for the synthesis of unsubstituted and substituted 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione compounds. Although these methods can be used to prepare unsubstituted and substituted 4-amino-62- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compounds, there remains a need for alternative or improved methods of preparing such compounds, particularly for use on an industrial scale.

Citation of any reference in section 2 of this application shall not be construed as an admission that such reference is prior art to the present invention.

4. Summary of the invention

The present invention provides an efficient process for the preparation of unsubstituted and substituted 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compounds, in particular unsubstituted 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione.

In one aspect, the present invention provides a process for preparing an unsubstituted or substituted 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindol-1, 3-dione compound of formula (I), or a pharmaceutically acceptable salt, solvate, including hydrate, or polymorph thereof:

wherein the process comprises cyclizing an N- (3-aminophthalicyl) -glutamine compound of formula (II) or an N- (3-aminophthalicyl) -isoglutamine compound of formula (IIA) or a salt thereof with a cyclizing agent of formula (V);

wherein R is¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) An alkynyl group; each of X and Y is independently an unsubstituted or substituted imidazolyl, benzimidazolyl or benzotriazolyl group. In some embodiments, R in formula (I) or (II)¹Is H.

In some embodiments, the cyclizing agent is a carbonyldiimidazole compound of formula (VI):

wherein each R is²、R³、R⁴、R⁵、R⁶And R⁷Independently H, alkyl, halogen, nitro, cyano, acyl, alkoxy, aryloxy, alkoxycarbonyl, or alkoxymethyl. In a specific embodiment, the carbonyldiimidazole compound is 1, 1' -carbonyldiimidazole (i.e., wherein each R in formula (VI) is²、R³、R⁴、R⁵、R⁶And R⁷Each H). In a further embodiment, the ratio of the compound of formula (II) to 1, 1' -carbonyldiimidazole is from about 1: 1 to about 1: 1.2.

In another embodiment, the cyclization reaction is carried out in acetonitrile. In another embodiment, the cyclization reaction is carried out in tetrahydrofuran. In a further embodiment, the cyclization reaction temperature is from about 80 ℃ to about 87 ℃. In another embodiment, the cyclization reaction time is from about 1 hour to about 5 hours.

In another aspect, the present invention provides a process for preparing an unsubstituted and substituted 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione compound of formula (I) or a pharmaceutically acceptable salt or solvate or polymorph thereof, wherein the process comprises the step of reacting 3-aminophthalic acid or salt thereof with a 3-aminoglutarimide compound of formula (X) or salt thereof in a solvent:

wherein R is¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl. In some embodiments, R in formula (I) or (X)¹Is H.

In certain embodiments, the reacting step is carried out in the presence of a base, an acid, or a combination thereof. In another embodiment, the reacting step is carried out in the presence of a base, which in some instances can be a trialkylamine, a substituted or unsubstituted imidazole, or a mixture thereof. In certain embodiments, the reacting step is carried out in the presence of a base, which can be an amine such as triethylamine, and an acid, which can be a carboxylic acid such as acetic acid. In certain embodiments, the molar ratio of triethylamine to acetic acid is about 1: 10 to about 1: 1.

In another embodiment, the solvent is acetonitrile. In a further embodiment, the reaction temperature is about 85-87 ℃. In a further embodiment, the reaction time is from about 5 hours to about 7 hours.

5. Detailed description of the invention

5.1 terminology

As used herein, unless otherwise specified, the terms "halo", "halogen", and the like are-F, -Cl, -Br, or-I.

As used herein, unless otherwise specified, the term "alkyl" or "alkyl group" is saturated, monovalent, unbranched or branchedA chain hydrocarbon chain. Examples of alkyl groups include, but are not limited to (C)₁-C₈) Alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, 2-methyl-1-butyl, 2-, Butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl, heptyl and octyl. An alkyl group may be unsubstituted or substituted with one or two suitable substituents.

The term "alkenyl" or "alkenyl group" as used herein, unless otherwise specified, refers to a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein. The double bond in an alkenyl group may be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to (C)₂-C₆) Alkenyl groups, such as vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4- (2-methyl-3-butenyl) -pentenyl. An alkenyl group may be unsubstituted or substituted with one or two suitable substituents.

The term "alkynyl" or "alkynyl group" as used herein, unless otherwise specified, refers to a monovalent, unbranched or branched hydrocarbon chain having one or more triple bonds therein. The triple bond in the alkynyl group may be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to (C)₂-C₈) Alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl and 4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substituted with one or two suitable substituents.

Unless otherwise specified, the term "substituted" as used herein to describe a compound or chemical group means that the compound isOr at least a portion of a chemical group is replaced with another chemical group. The other chemical group may be any suitable substituent that does not render the synthesis, pharmaceutical use, or intermediates useful in the preparation of the compounds of the present invention ineffective. Examples of suitable substituents include, but are not limited to: (C)₁-C₈) An alkyl group; (C)₂-C₈) An alkenyl group; (C)₂-C₈) An alkynyl group; an aryl group; (C)₂-C₅) A heteroaryl group; (C)₁-C₆) A heterocycloalkyl group; (C)₃-C₇) A cycloalkyl group; o- (C)₁-C₈) An alkyl group; o- (C)₂-C₈) An alkenyl group; o- (C)₂-C₈) An alkynyl group; an O-aryl group; CN; OH; an oxy group; halogen; c (O) OH; a CO halogen; o (CO) halogen; CF (compact flash)₃、N₃；NO₂、NH₂；NH((C₁-C₈) Alkyl groups); n ((C)₁-C₈) Alkyl radical)₂(ii) a NH (aryl); n (aryl)₂；(CO)NH₂；(CO)NH((C₁-C₈) Alkyl groups); (CO) N ((C)₁-C₈) Alkyl radical)₂(ii) a (CO) NH (aryl); (CO) N (aryl)₂；O(CO)NH₂；NHOH；NOH((C₁-C₈) Alkyl groups); NOH (aryl); o (CO) NH ((C)₁-C₈) Alkyl groups); o (CO) N ((C)₁-C₈) Alkyl radical)₂(ii) a O (co) NH (aryl); o (CO) N (aryl)₂；CHO；CO((C₁-C₈) Alkyl groups); CO (aryl); c (O) O ((C)₁-C₈) Alkyl groups); c (O) O (aryl); o (CO) ((C)₁-C₈) Alkyl) -; o (co) (aryl); o (CO) O ((C)₁-C₈) Alkyl groups); o (CO) O (aryl); s- (C)₁-C₈) An alkyl group; s- (C)₁-C₈) An alkenyl group; s- (C)₁-C₈) Alkynyl and S-aryl. One skilled in the art will readily select suitable substituents based on the stability and pharmaceutical and synthetic activity of the compounds of the present invention.

Unless otherwise specified, a composition described herein as "substantially free" of a compound refers to a composition that contains less than about 20% by weight, more preferably less than 10% by weight, even more preferably less than 5% by weight, and most preferably less than 3% by weight of the compound.

As used herein, unless otherwise specified, the term "stereomerically pure" refers to a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having one chiral center is substantially free of the opposite enantiomer of the compound. Stereomerically pure compositions of compounds having two chiral centers are substantially free of other diastereomers of the compound. A typical stereomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound; more preferably, it comprises greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound; even more preferably, contains greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound; most preferably, it contains greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

The term "enantiomerically pure" as used herein, unless otherwise specified, refers to an enantiomerically pure composition of a compound having one chiral center.

The term "racemic" or "racemate" as used herein, unless otherwise specified, refers to about 50% of one enantiomer relative to all chiral centers in the molecule and about 50% of the corresponding enantiomer. The present invention includes all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched and racemic mixtures of all of the compounds of the invention.

The terms "process of the invention" or "method of preparation" or "method for preparation" as used herein, unless otherwise specified, refer to the process disclosed herein for preparing the compounds of the invention. Variations on the methods disclosed herein (e.g., starting materials, reagents, protecting groups, solvents, temperatures, reaction times, purity) are also within the scope of the invention.

As used herein, unless otherwise specified, the terms "add," "react," and the like, refer to the reaction of one reactant, solvent, catalyst, reactive group, or the like, with another reactant, solvent, catalyst, reactive group, or the like. The reactants, reagents, solvents, catalysts, reactive groups, etc. may be added separately, simultaneously or separately and may be added in any order. These materials may be added with or without heating, and optionally may be added under an inert environment. "reacting" may refer to an in situ generation or an intramolecular reaction in which the reactive groups are in the same molecule.

As used herein, unless otherwise specified, a reaction that is "substantially complete" or allowed to "substantially complete" refers to a reaction that contains greater than about 80% yield, more preferably greater than about 90% yield, even more preferably greater than about 95% yield, and most preferably greater than about 97% yield of the desired product.

The term "pharmaceutically acceptable salt" as used herein includes, but is not limited to, salts of acidic or basic groups which may be present in the compounds of the present invention, unless otherwise specified. The naturally basic compounds of the invention are capable of forming a wide variety of salts with a wide variety of inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable salts of these basic compounds are those that form salts with pharmaceutically acceptable anions, including, but not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, acid tartrate, bromide, camsylate, carbonate, chloride, bromide, iodide, citrate, dihydrochloride, edetate, edisylate, etolate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, myristate (muscoate), naphthalenesulfonate, nitrate, hydroxpyrate, glycolate, acetate, and acetate salts of these acids, Dexpanthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, succinate, sulfate, tannate, tartrate, chlorotheophylline, triethiodide, and pamoate. In addition to the acids mentioned above, the compounds of the invention containing an amino group may also form pharmaceutically acceptable salts with a variety of amino acids. Naturally acidic compounds of the invention are capable of forming base salts with a variety of pharmaceutically acceptable cations. Non-limiting examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

The term "hydrate" as used herein, unless otherwise specified, refers to a compound of the present invention or a salt thereof, which further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term "solvate" as used herein, unless otherwise specified, refers to a solvate formed by the combination of one or more solvent molecules and a compound of the present invention. The term "solvate" includes hydrates (e.g., monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

The term "polymorph" as used herein, unless otherwise specified, refers to a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectroscopic properties.

As used herein, unless otherwise specified, the phrase "a disease or condition associated with an abnormally high level or activity of TNF- α" refers to a disease or condition that does not produce, persist, or cause symptoms if the level or activity of TNF- α is low, or that can be prevented or treated by reducing the level or activity of TNF- α.

The phrase "treating" as used herein, unless otherwise specified, refers to the act of taking a patient suffering from a particular disease or disorder, which reduces the severity or symptoms of the disease or disorder, or slows or delays the progression or symptoms of the disease or disorder.

The acronyms or symbols of the groups or reagents have the following definitions: HPLC ═ high performance liquid chromatography, CH₃CN is acetonitrile; DMF, DMSO, dimethyl sulfoxide, THF, tetrahydrofuran, CH₂Cl₂Dichloromethane and CDI 1, 1' -carbonyldiimidazole.

If there is a contradiction between the illustrated structure and the name of the structure, the illustrated structure is taken as the main point. Moreover, if the stereochemistry of a structure or a portion thereof is not indicated with, for example, bold or dashed lines, the structure or portion thereof is to be understood as encompassing all stereoisomers of the same.

The present invention may be understood more fully by reference to the following detailed description and illustrative examples, which are intended to illustrate non-limiting embodiments of the invention.

5.2 methods of the invention

The present invention provides a process for the preparation of unsubstituted and substituted 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compounds. In general, the methods of the present invention may comprise an improved or efficient process for the large scale or commercial production of unsubstituted and substituted 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compounds.

Unsubstituted and substituted 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compounds can be used to prepare pharmaceutical compositions and/or dosage forms for the treatment of a variety of diseases and conditions, including but not limited to inflammation, autoimmune diseases, cancer, heart disease, genetic diseases, allergy, osteoporosis, and lupus. Typically, the pharmaceutical composition may comprise at least one of a 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compound, or a pharmaceutically acceptable salt, solvate, polymorph, or stereoisomer thereof. The pharmaceutical compositions can be administered to patients receiving treatment for a variety of diseases and conditions. Optionally, the pharmaceutical composition may further comprise at least one carrier, excipient, diluent, second active agent, or combination thereof. In some embodiments, the pharmaceutical compositions are used to prepare individual unit dosage forms. The unit dosage form is suitable for administration to a patient orally, mucosally (sublingual, nasal, vaginal, bladder, rectal, pyloric, ocular, buccal, or otic), parenterally (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topically (e.g., eye drops or other ophthalmic formulations), transdermally, or transdermally. Non-limiting examples of dosage forms include tablets, caplets, capsules (e.g., soft elastic gelatin capsules), cachets, lozenges, troches, dispersions, suppositories, powders, aerosols (e.g., nasal sprays or inhalants), gels, liquid dosage forms suitable for oral administration to a patient or mucosal administration to a patient including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions and elixirs, liquid dosage forms suitable for parenteral administration to a patient, eye drops or other ophthalmic preparations suitable for topical administration, and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted into liquid dosage forms suitable for parenteral administration to a patient.

In some embodiments, the present invention provides a method of preparing a 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, or stereoisomer thereof:

the process comprises cyclizing an N- (3-aminophthalicyl) -glutamine compound of formula (II), an N- (3-aminophthalicyl) -isoglutamine compound of formula (IIA), or a salt thereof, with a cyclizing agent,

wherein R is¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl.

In one embodiment, R in formula (I) and/or (II)¹Is H. In a particular embodiment, R in formula (I) and/or (II)¹Is (C)₁-C₈) An alkyl group. In a further embodiment, R in formula (I) and/or (II)¹Is methyl. In another embodiment, the solvate is a hydrate.

The cyclization of the compound of formula (II) with the cyclizing agent is carried out in a solvent such as acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, and combinations thereof. In one embodiment, the solvent is acetonitrile. In another embodiment, the solvent is boiling acetonitrile.

The reaction temperature may be any temperature for the cyclization reaction as understood by one of ordinary skill in the art. For example, in certain embodiments, the cyclization reaction temperature varies between about 20 ℃ to 100 ℃. In some embodiments, the cyclization reaction temperature is about 50 ℃ to 90 ℃. In another embodiment, the cyclization reaction temperature is about 80 ℃ to 87 ℃. In a specific embodiment, the cyclization reaction temperature is the boiling point of acetonitrile (i.e., 81-82 ℃ at 1 atm).

The cyclization reaction time can be any time period for the cyclization reaction as understood by one of ordinary skill in the art. For example, in certain embodiments, the cyclization reaction time varies between about 1 to 24 hours depending on the reaction temperature. Generally, the higher the reaction temperature, the shorter the reaction time. In one embodiment, the solvent is acetonitrile, the reaction temperature is about 80 ℃ to 87 ℃, and the reaction time is about 1 to 5 hours.

The cyclizing agent is any chemical species capable of causing a ring-forming reaction between the amino group and the carboxyl group in formula (II) or (IIA). In some embodiments, the cyclizing agent has the formula:

wherein X and Y are independently unsubstituted and substituted imidazolyl, benzimidazolyl or benzotriazolyl. The cyclizing agent of formula (V) can be purchased from a commercial supplier or prepared by any method known to one of ordinary skill in the art. For example, the cyclizing agent of formula (V) can be prepared by reacting phosgene (COCl)₂) And unsubstituted and substituted 1H-imidazole compounds, 1H-benzimidazole or 1H-benzotriazole. The reaction between phosgene and 1H-imidazole compounds is disclosed in Batey et al, Tetrahedron Lett., 1998, 39, 6267. The reaction between phosgene and 1H-benzotriazole is disclosed in Katritzky et al, J.org.chem., 1997, 62, 4155.

In some embodiments, the cyclizing agent is a carbonyldiimidazole having the formula:

wherein R is²、R³、R⁴、R⁵、R⁶And R⁷Each of which is independently H, alkyl, halo, nitro, cyano, acyl, alkoxy, aryloxy, alkoxycarbonyl, or alkoxymethyl.

The carbonyldiimidazole compound of formula (VI) can be purchased from commercial suppliers or prepared by any method known to those of ordinary skill in the art. For example, the carbonyldiimidazole of formula (VI) can be prepared by phosgene (COCl)₂) And an unsubstituted or substituted 1H-imidazole compound or a combination thereof. Some non-limiting examples of 1H-imidazole compounds suitable for the present invention include 1H-imidazole, 2-methyl-1H-imidazole, 1H-imidazole-5-lactaldehyde, 2-ethyl-1H-imidazole, 2-isopropyl-1H-imidazole, 2-ethyl-5-methyl-1H-imidazole, 2-propyl-1H-imidazoleThe base-1H-imidazole, 2-nitro-1H-imidazole, 5-nitro-1H-imidazole, methyl-1H-imidazole-5-carboxylate, 4- (2-methoxyethyl) -1H-imidazole, 2-methyl-5-nitro-1H-imidazole, and 5-methyl-4-nitro-1H-imidazole, all of which are commercially available from suppliers such as Aldrich Chemicals, Milwaukee, Wis., or are prepared by methods well known to those of ordinary skill in the art. Non-limiting examples of carbonyldiimidazole compounds include 1,1 ' -carbonyldiimidazole, 2 ' -dimethyl-1, 1 ' -carbonyldiimidazole, 2 ' -diethyl-1, 1 ' -carbonyldiimidazole, 2 ' -diisopropyl-1, 1 ' -carbonyldiimidazole and 2, 2 ' -dinitro-1, 1 ' -carbonyldiimidazole, all of which are commercially available from suppliers such as Aldrich Chemicals, Milwaukee, Wis, or prepared by the methods described above. In one embodiment, the carbonyldiimidazole compound is 1, 1' -carbonyldiimidazole.

In a further embodiment, the cyclizing agent is selected from the group consisting of formula (V), SOCl₂、POCl₃、SOCl₂Derivative of (5) and POCl₃And combinations thereof. In addition to the cyclizing agent, the cyclization reaction can be further accelerated or catalyzed using a base. The base is selected from organic amines such as triethylamine, pyridine derivatives and combinations thereof.

In a specific embodiment, the 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compound of formula (I) can be prepared by cyclizing an N- (3-aminophthalicyl) -glutamine compound of formula (II) or salt thereof with 1, 1' -Carbonyldiimidazole (CDI) in refluxing acetonitrile for about 3 hours, as depicted in scheme A below. Alternatively, the same reaction can be carried out in N-methylpyrrolidone or tetrahydrofuran at room temperature for about 13 to 15 hours. In some embodiments, R in scheme A¹Is H.

Procedure A

The ratio of the compound of formula (II) to 1, 1' -carbonyldiimidazole can be any ratio that one of ordinary skill in the art would understand to be useful in a cyclization reaction. For example, the ratio of the compound of formula (II) and 1, 1' -carbonyldiimidazole can be from about 2: 1 to about 1: 2. In some embodiments, the ratio of the compound of formula (II) to 1, 1' -carbonyldiimidazole is from about 1: 1 to about 1: 1.5. In other embodiments, the ratio of the compound of formula (II) to 1, 1' -carbonyldiimidazole may be from about 1: 1 to about 1: 1.2. In one embodiment, the cyclization of formula (II) with 1, 1' -carbonyldiimidazole is carried out in acetonitrile for 1 to 24 hours. In another embodiment, the cyclization of formula (II) is carried out in refluxing acetonitrile for 3 hours.

In another embodiment, 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compounds of formula (I) can be prepared by cyclizing an N- (3-aminophthalicyl) -isoglutamide compound of formula (IIA) with 1,1 '-Carbonyldiimidazole (CDI) in a solvent such as acetonitrile, N-methylpyrrolidone, and tetrahydrofuran, as depicted in scheme A' below. The reaction may be carried out at a temperature ranging from about room temperature to about 150 ℃ for about 30 minutes to about 24 hours.

Process A'

In one embodiment, the compound of formula (I) may be a free amine. Optionally, the free amine of formula (I) can be converted to the acid salt by reacting the free amine of formula (I) with the corresponding acid in a molar ratio of about 1: 1. Some non-limiting examples of suitable acids include methanesulfonic acid, trifluoroacetic acid, 4- (trifluoromethyl) benzoic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid. In one embodiment, 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione of formula (I) is converted into the hydrochloride salt with hydrochloric acid at a temperature of about 0 ℃ to about 22 ℃.

If a racemic compound of formula (I) is desired, a racemic N- (3-aminophthalicyl) -glutamine compound of formula (II) may be used in the cyclization reaction. Conversely, if an enantiomerically pure compound of formula (I) is desired, enantiomerically pure N- (3-aminophthalicyl) -glutamine of formula (II) may be used. Alternatively, if an enantiomerically pure compound of formula (I) is desired, a racemic mixture of formula (I) may be prepared and then resolved into the enantiomers by conventional resolution techniques such as biological resolution and chemical resolution. Typically, biological resolution uses microorganisms that metabolize one particular enantiomer while leaving the other enantiomer alone. In chemical resolution, the racemic mixture is converted into two diastereomers, which can be separated by conventional techniques such as fractional crystallization and chromatography. After separation, the diastereomers may be converted back to enantiomers, respectively.

The compounds of formula (II) may be prepared by any method known to those of ordinary skill in the art. For example, as depicted in scheme B below, compounds of formula (II) can be prepared by reducing the nitro group in compounds of formula (III) to an amine group:

procedure B

Wherein R is¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl. In some embodiments, R in scheme B¹Is H.

Similarly, as depicted in scheme B' below, compounds of formula (IIA) can be prepared by reducing the nitro group in compounds of formula (IIIA) to an amine group:

process B'

In scheme B and scheme B' above, the compounds of formula (III) and (IIIA) can be reduced to compounds of formula (II) and (IIA), respectively, by using art-known reducing agents that can reduce the nitro group to a primary amine. Some non-limiting examples of these reducing agents include hydrogenation catalysts (catalytic hydrogenation), reducing metals in acids such as hydrochloric acid and acetic acid, sodium sulfide in ammonium hydroxide solution, zinc in ammonium formate solution, magnesium in hydrazine monocarboxylate solution, and tin dichloride in dilute hydrochloric acid solution. Some non-limiting examples of suitable hydrogenation catalysts include palladium metal (Pd), platinum metal (Pt), and derivatives and complexes of Pd and Pt. The hydrogenation catalyst may be dissolved in a solvent; or dispersed or coated on the surface of a catalyst support such as carbon and inorganic particles such as alumina, silica, aluminum silicide, and the like. Some non-limiting examples of suitable reducing metals include iron, zinc amalgam, zinc, and tin. In a specific embodiment, the reducing agent is a hydrogenation catalyst. In a further embodiment, the catalyst is a Pd catalyst. In another embodiment, the catalyst is 5% Pd/C. In another embodiment, the catalyst is 10% Pd/C. In addition, wet or dry hydrogenation catalysts may be used.

Catalytic hydrogenation is typically carried out at a hydrogen pressure such that the reaction is substantially complete. In particular embodiments, the hydrogen pressure in the catalytic hydrogenation reaction is about 2.76 bar (i.e., 40psi or 276 kPa) to 4.14 bar (i.e., 60psi or 414 kPa).

In one embodiment, the catalytic hydrogenation is carried out at ambient temperature. Catalytic hydrogenation is generally carried out until the reaction is substantially complete. In a specific embodiment, the catalytic hydrogenation is carried out at a temperature of about 15 ℃ to about 30 ℃ for about 1 to about 24 hours. In a further embodiment, the catalytic hydrogenation is carried out at a temperature of about 18 ℃ to 24 ℃ for about 2 to 3 hours.

In one embodiment, the catalytic hydrogenation is carried out in methanol containing 10% Pd/C for about 2 to 3 hours at a temperature of about 18 ℃ to 24 ℃. Either wet or dry hydrogenation catalysts may be used. In a further embodiment, the catalytic hydrogenation is carried out at a pressure of about 40psi (i.e., 2.76 bar or 276 kpa) to 50psi (i.e., 3.45 bar or 345 kpa).

The catalytic hydrogenation may be carried out in a solvent. In one embodiment, the catalytic hydrogenation is carried out in a protic solvent, such as an alcohol, water, and combinations thereof. In a further embodiment, the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol and combinations thereof. In another embodiment, the catalytic hydrogenation is carried out in a nonpolar, aprotic solvent such as 1, 4-dioxane. In another embodiment, the catalytic hydrogenation is carried out in a polar, aprotic solvent such as acetone, DMSO, DMF, and THF. In one embodiment, the solvent is a protic solvent. In a further embodiment, the solvent for catalytic hydrogenation is methanol. In further embodiments, a mixture of solvents may be used.

If racemic compounds of formula (II) or (IIA) are desired, racemic compounds of formula (III) or (IIIA) can be used. Conversely, if an enantiomerically pure compound of formula (II) or (IIA) is desired, an enantiomerically pure compound of formula (III) or (IIIA) may be used. Alternatively, if an enantiomerically pure compound of formula (II) or (IIA) is desired, a racemic mixture of formula (II) or (IIA) may be prepared and then resolved into enantiomers by conventional resolution techniques such as biological resolution and chemical resolution.

The compounds of formula (III) may be prepared by any method known to those of ordinary skill in the art. For example, as shown in scheme C below, the compound of formula (III) can be prepared by reacting 3-nitrophthalic anhydride with glutamine of formula (IV). R¹As defined above. In some embodiments, R in scheme C¹Is H.

Procedure C

Similarly, as shown in scheme C' below, 3-nitrophthalic acid can be prepared by reactingThe reaction of formic anhydride and isoglutamine of formula (IVA) produces the compound of formula (IIIA). R¹As defined above. In some embodiments, R in scheme C¹Is H.

Process C'

The reaction between 3-nitrophthalic anhydride and glutamine of formula (IV) or isoglutamine of formula (IVA) can be carried out in a solvent such as acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide and combinations thereof. In one embodiment, the solvent is dimethylformamide.

The reaction temperature may be any temperature as understood by one of ordinary skill in the art to be useful for the reactions in scheme C and scheme C'. For example, in certain embodiments, the reaction temperature of the 3-nitrophthalic anhydride and formula (IV) or formula (IVA) is from about 20 ℃ to about 90 ℃. In some embodiments, the reaction temperature is from about 40 ℃ to about 90 ℃. In other embodiments, the reaction temperature is from about 60 ℃ to about 90 ℃. In a further embodiment, the reaction temperature is from about 80 ℃ to about 90 ℃.

The reaction time may be any time as understood by one of ordinary skill in the art to be useful for the reactions in scheme C and scheme C'. For example, the reaction time may vary from about 1 hour to 24 hours depending on the reaction temperature. Generally, the higher the reaction temperature, the shorter the reaction time. In a specific embodiment, the reaction time is about 8 hours at a reaction temperature of about 80 ℃ to about 90 ℃.

If racemic compounds of formula (III) or (IIIA) are desired, racemic glutamines of formula (IV) or (IVA) can be used. Conversely, if an enantiomerically pure compound of formula (III) or (IIIA) is desired, an enantiomerically pure glutamine of formula (IV) or (IVA) may be used. Non-limiting examples of glutamines of formula (IV) include D-glutamine and L-glutamine, both of which are commercially available from suppliers such as Aldrich, Milwaukee, Wis. Alternatively, if an enantiomerically pure compound of formula (III) or (IIIA) is desired, a racemic mixture of formula (III) or (IIIA) may be prepared and then resolved into enantiomers by conventional techniques such as biological resolution and chemical resolution.

3-Nitrophthalic anhydride may be purchased from a supplier such as Aldrich Chemical, or prepared by any method known in the art. Further, the compound of formula (VII) can be produced by reacting maleic anhydride with glutamine of formula (IV) according to the reaction conditions between the above-mentioned 3-nitrophthalic anhydride and the glutamine compound of formula (IV).

Alternatively, the compounds of formula (III) are prepared according to the procedures described in scheme D below. With respect to scheme D, R¹As defined above, R⁸Is an alkyl group such as t-butyl or an aralkyl group such as benzyl. In some embodiments, R in scheme D¹Is H, R⁸Is a tert-butyl group. In other embodiments, R in scheme D¹Is H, R⁸Is benzyl.

Procedure D

With respect to scheme D above, 3-nitrophthalimide can be reacted with ethyl chloroformate in the presence of a catalyst such as triethylamine in a solvent to form 3-nitro-N-ethoxycarbonylphthalimide. Some non-limiting examples of suitable solvents include acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, and combinations thereof. In one embodiment, the solvent is dimethyl sulfoxide. The reaction temperature may be any temperature understood by one of ordinary skill in the art to be useful in the present invention. For example, in certain embodiments, the reaction temperature is from about 0 ℃ to about 5 ℃. The reaction time may be any time available to be reacted as understood by one of ordinary skill in the art. For example, the reaction time may vary from about 1 hour to about 24 hours, depending on the reaction temperature. Generally, the higher the reaction temperature, the shorter the reaction time. In a specific embodiment, the reaction time is about 4 hours at 0 ℃ to 5 ℃.

Tert-butyl or benzyl N- (3-nitrophthaloyl) -glutamine of formula (IX) is commercially available; or by reacting 3-nitro-N-ethoxycarbonyl-phthalimide with glutamine tert-butyl or benzyl ester of formula (VIII) or an acid salt thereof, such as the hydrochloride salt, in a solvent in the presence of a catalyst such as triethylamine¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) An alkynyl group; r⁸Is tert-butyl or benzyl. In some embodiments, a racemic mixture of glutamine tert-butyl ester acid is used to prepare the compound of formula (IX). In other embodiments, L-glutamine tert-butyl ester acid is used to prepare the compound of formula (IX). In a further embodiment, D-glutamine tert-butyl ester acid is used to prepare the compound of formula (IX). Some non-limiting examples of suitable solvents include acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, and combinations thereof. In one embodiment, the solvent is tetrahydrofuran. The reaction temperature may be any temperature that can be used in the present reaction as understood by one of ordinary skill in the art. For example, in certain embodiments, the reaction temperature is from about 25 ℃ to about 100 ℃. The reaction time may be any time that can be used for the present reaction as understood by one of ordinary skill in the art. For example, the reaction time may vary from about 1 hour to about 48 hours depending on the reaction temperature. Generally, the higher the reaction temperature, the shorter the reaction time. In a specific embodiment, the reaction time is about 24 hours at about 65 ℃ to about 66 ℃.

Reaction of hydrogen chloride and tert-butyl N- (3-nitrophthaloyl) -glutamine of formula (IX) in a solvent can give the compound of formula (III). Some non-limiting examples of suitable solvents include acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, and combinations thereof. In one embodiment, the solvent is dichloromethane. The reaction temperature may be any temperature that can be used in the present reaction as understood by one of ordinary skill in the art. For example, in certain embodiments, the reaction temperature is from about 0 ℃ to about 100 ℃. The reaction time may be any time that can be used for the present reaction as understood by one of ordinary skill in the art. For example, the reaction time varies from about 1 hour to 24 hours depending on the reaction temperature. Generally, the higher the reaction temperature, the shorter the reaction time. In a specific embodiment, the reaction time is about 16 hours at about 20 ℃ to about 25 ℃.

With respect to scheme D, if a racemic compound of formula (III) is desired, racemic tert-butyl N- (3-nitrophthaloyl) -glutamine of formula (VIII) can be used. Conversely, if an enantiomerically pure compound of formula (III) is desired, enantiomerically pure tert-butyl N- (3-nitrophthaloyl) -glutamine of formula (VIII) can be used. Alternatively, if an enantiomerically pure compound of formula (III) is desired, a racemic mixture of formula (III) may be prepared and then resolved into the enantiomers by conventional techniques, such as biological and chemical resolution. Typically, biological resolution uses microorganisms that metabolize one particular enantiomer while leaving the other enantiomer behind. In chemical resolution, a racemic mixture is converted into two diastereomers, which can be separated by conventional techniques such as fractional crystallization and chromatography. After separation, the diastereomers may be converted back to enantiomers, respectively.

In some embodiments, the compound of formula (IIIA) is prepared according to the methods described in scheme D', which are analogous to scheme D, below. With respect to formulae (VIIIA), (IXA) and (IIIA), R¹And R⁸As defined above. In some embodiments, R in scheme D¹Is H, R⁸Is a tert-butyl group. In other embodimentsR in scheme D¹Is H, R⁸Is benzyl.

Process D'

Alternatively, the 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof can be prepared by reacting 3-aminophthalic acid or a salt thereof with a 3-aminoglutarimide compound of formula (X) or a salt thereof in a solvent:

wherein R is¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl. In some embodiments, R in formula (X)¹Is H.

3-aminoglutarimide compounds are commercially available from suppliers such as Evotec OAI, Hamburg, Germany; or according to the methods disclosed in the literature, for example, Capitosti et al, Organic Letters, 2003, volume 5, No. 16, pages 2865-2867. In some embodiments, the compound of formula (X) 3-aminoglutarimide compound is 3-aminoglutarimide (i.e., R in formula (X))¹Is H) or a salt thereof. Some non-limiting examples of suitable salts of formula (X) include carboxylates, methanesulfonates, trifluoroacetates, 4- (trifluoromethyl) benzoates, p-toluenesulfonates, hydrochlorides, hydrobromides, nitrates, sulfates and phosphates.

The above condensation or coupling reaction between 3-aminophthalic acid or a salt thereof and the compound of formula (X) or a salt thereof may be carried out in the presence of a catalyst. The catalyst may be a base, an acid such as a carboxylic acid, or a combination thereof. In some embodiments, the catalyst is or comprises a base. Some non-limiting examples of suitable bases include alkali metal hydroxides, alkali metal carboxylates (e.g., sodium acetate), alkali metal carbonates or bicarbonates (e.g., sodium bicarbonate), heterocyclic bases (e.g., substituted and unsubstituted pyrrolidines, pyrrolidones, piperidines, piperidones, pyrroles, pyridines, imidazoles, benzimidazoles, benzotriazoles, and the like), amines, and combinations thereof. In some embodiments, the catalyst is or contains an amine. Non-limiting examples of suitable amines include alkylamines (such as ethylamine), dialkylamines (such as diethylamine), trialkylamines (such as triethylamine and N, N-diisopropylethylamine), arylamines (such as aniline), diarylamines (such as diphenylamine), alkylarylamines (such as N-methylaniline), triarylamines (such as triphenylamine), dialkylarylamines (such as N, N-dimethylarylamine), and alkyldiarylamines (such as N-methyldiphenylamine). In one embodiment, the catalyst is or comprises triethylamine, unsubstituted imidazole, or a combination thereof.

In certain embodiments, the catalyst is or comprises a carboxylic acid of formula (XI):

R⁸-CO₂H (XI)

wherein R is⁸Is an alkyl, aryl, alkaryl, aralkyl, heterocyclic group, or combinations thereof. In some embodiments, the carboxylic acid is or comprises a fatty carboxylic acid such as acetic acid. In a further embodiment, the catalyst comprises at least one amine and at least one carboxylic acid of formula (XI) disclosed herein. In a specific embodiment, the catalyst comprises triethylamine and acetic acid.

The solvent used for the condensation reaction may be any solvent capable of dispersing or dissolving 3-aminophthalic acid or a salt thereof and the 3-aminoglutarimide compound of the formula (X) or a salt thereof. Non-limiting examples of suitable solvents include acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, toluene, isopropyl acetate, isopropanol, N-butanol, and combinations thereof. In one embodiment, the solvent is acetonitrile.

The condensation reaction temperature may be any temperature that is useful for the reaction as understood by one of ordinary skill in the art. For example, in certain embodiments, the condensation reaction temperature is from about 25 ℃ to about 100 ℃.

The condensation reaction time may be any time that is useful for the present reaction as understood by one of ordinary skill in the art. For example, the reaction time may vary from about 1 hour to about 48 hours depending on the reaction temperature. Generally, the higher the reaction temperature, the shorter the reaction time. In particular embodiments, the reaction time at a reaction temperature of about 80 ℃ to about 90 ℃ is about 5 hours to about 7 hours.

In one embodiment, the compound of formula (I) is 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (i.e., R in formula (I)) prepared according to scheme E below¹Is H). With respect to scheme E, 3-aminophthalic acid hydrochloride (i.e., Compound (1)) and 3-aminoglutarimide (i.e., R in formula (X))¹Is H) hydrochloric acid (i.e., compound (2)) in a solvent such as acetonitrile in the presence of a catalyst comprising triethylamine and acetic acid. In some embodiments, the molar ratio of triethylamine to acetic acid is about 1: 10 to about 10: 1. In another embodiment, the molar ratio of triethylamine to acetic acid is about 1: 10 to about 1: 1. In a further embodiment, the molar ratio of triethylamine to acetic acid is about 1: 2.

Procedure E

The 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione compound of formula (I) can be purified by any conventional purification technique, such as recrystallization, extraction, chromatography, and the like. In some embodiments, the compound of formula (I) is purified by recrystallization. In other embodiments, the compound of formula (I) is 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (i.e., R in formula (I))¹Is H), the compound can be prepared by reacting with a compound containingThe solvent mixture of dimethyl sulfoxide and water is recrystallized together to obtain the purified product. In a further embodiment, the volume ratio of dimethyl sulfoxide to water in the solvent mixture is from about 1: 10 to about 10: 1. In a further embodiment, the volume ratio of dimethyl sulfoxide to water in the solvent mixture is from about 1: 4 to about 1: 8.

The specific embodiments of the present invention are illustrated by the syntheses of examples 1-17 according to schemes A-E and variations thereof. Variations in variables including, but not limited to, reaction solvent, reaction time, reaction temperature, reaction reagents, starting reactants, and functional groups in embodiments of the synthesis of 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione or its acid salt will be apparent to those of ordinary skill in the art.

6. Examples of the embodiments

EXAMPLE 1 preparation of N- (3-Nitrophthaloyl) -Glutamine according to scheme C

A mixture of DMF (37L), 3-nitrophthalic anhydride (4080g, 21.1 moles) and L-glutamine (3020g, 20.7 moles) was charged to a round bottom flask equipped with a mechanical stirrer, condenser, thermometer, nitrogen inlet and heating mantle. The reaction mixture was stirred at 80-87 ℃ for 8 hours. The reaction temperature was kept below 90 ℃. The progress of the reaction was monitored by HPLC using a Waters Nova-Pak C18 column (3.9 × 150mm, particle size 4 μm, UV wavelength 240nm, retention time 3.64 min) and a mixture of 10/90 acetonitrile and 0.1% aqueous phosphoric acid in volume ratio as the wash solution at a flow rate of 1 ml/min. After completion of the reaction, the reaction mixture was cooled to room temperature and then concentrated to an oil (about 90% DMF removed) under reduced pressure (400 mtorr pressure in the pump) at 40 ℃ in a hot bath. The oil was stirred with water (39.7L) for 6 hours to form a slurry. The slurry was filtered to remove solids, washed with water (8.8L), dried in air and then dried in a vacuum oven at 60 ℃ and a pressure of < 1 mm. The crude product obtained was 4915g (HPLC, 92.9% purity)). The crude product was further purified by further dispersing the crude product in ethyl acetate at a ratio of 10mL ethyl acetate to 1g crude product. After the dispersion was stirred overnight, it was filtered and the filtered solid was dried to give 4780g (70%) of the product. The product purity was determined by HPLC at 99.62%, using a Waters Nova-Pak/C18 column (3.9 × 150mm, particle size 4 μm, UV wavelength 240nm, retention time 5 min) and a mixture of acetonitrile and 0.1% aqueous phosphoric acid in a volume ratio of 10: 90 as the wash solution, at a flow rate of 1 ml/min. The product is in DMSO-d₆For middle use¹H NMR spectrum characterization, exhibiting the following chemical shifts (, ppm): 13.32(b, 1H), 8.33(d, J ═ 7.9Hz, 1H), 8.22(d, J ═ 7.4Hz, 1H), 8.11(t, J ═ 7.8Hz, 1H), 7.20(s, 1H), 6.47(s, 1H), 4.83-4.77(dd, J ═ 4.6 and 9.7Hz, 1H), 2.37-2.12(m, 4H); and use of¹³C NMR characterization, exhibiting the following chemical shifts (, ppm): 173.24, 170.05, 165.44, 162.77, 144.47, 136.71, 133.00, 128.85, 127.27, 122.55, 51.88, 31.32, 23.89. The melting point of the product is 180-182 ℃. Elemental analysis gave the following weight percent results: c, 48.75; h, 3.48; n, 13.07, their preparation and C₁₃H₁₁N₃O₇The calculated weight percentages are equivalent to: c, 48.60; h, 3.45; and N, 13.08.

Example 2 preparation of N- (3-aminophthalicyl) -glutamine according to scheme B

A mixture of the mixture of example 1 (4780, 14.88 moles), 10% Pd/C (120g), and methanol (44L) was hydrogenated in a 100L hydrogenation reactor at 50psi for 2.5 hours. The progress of the reaction was monitored by HPLC using a Waters Nova-Pak C18 column (3.9X 150mm, particle size 4 μm, UV wavelength 240nm, retention time 3.64 min) and a wash of acetonitrile in a volume ratio of 10: 90 and 0.1% aqueous phosphoric acid at a flow rate of 1 ml/min. The mixture was filtered through a pad of celite, which was washed with methanol (6L). The filtrate was concentrated in vacuo to give a viscous material. The viscous mass was stirred with ethyl acetate (22L)Stirring overnight to form a slurry. The slurry was filtered and the yellow solid filtered off was washed with ethyl acetate (10L). The yellow solid was dried in air and then dried in a vacuum oven at 60 ℃ and a pressure < 1mm to give 4230g of product. The purity of the product determined by HPLC was 99.75%, using a Waters Nova-Pak C18 column (3.9X 150mm, particle size 4 μm, UV wavelength 240nm, retention time 3.64 min) and a mixture of acetonitrile and 0.1% aqueous phosphoric acid in a volume ratio of 10: 90 as the wash liquid at a flow rate of 1 ml/min. The product is in DMSO-d₆For middle use¹H NMR spectrum characterization, exhibiting the following chemical shifts (, ppm): 13.10(b, 1H), 7.50-7.43(dd, J ═ 7.0 and 8.4Hz, 1H), 7.24(s, 1H), 7.03-6.98(dd, J ═ 5.0 and 8.4Hz, 2H), 6.75(s, 1H), 6.52(s, 2H (, 4.70-4.64(dd, J ═ 4.5 and 10.5Hz, 1H), 2.41-2.04(m, 4H), and combinations thereof¹³C NMR characterization, exhibiting the following chemical shifts (, ppm): 173.16, 170.81, 168.94, 167.68, 146.70, 135.41, 132.07, 121.63, 110.93, 108.68, 50.77, 31.38, 24.08. The melting point of the product was 177-179 ℃. Elemental analysis gave the following weight percent results: c, 53.61; h, 4.47; n, 14.31; it is with C₁₃H₁₃N₃O₇₅The calculated weight percentages are equivalent to: c, 53.60; h, 4.50; n, 14.4.

Example 3 preparation of 4-amino-2- (2, 6-dioxo-3-piperidyl) ethylindole-1, 3-dione according to scheme A

A mixture of acetonitrile (42L), the compound of example 2 (2120g, 7.28 moles) was added to a round bottom flask equipped with a mechanical stirrer, condenser, nitrogen inlet and heating mantle to form a solution. While the solution was stirred and heated to about 40-45 ℃, 1' -carbonyldiimidazole (1290g, 7.95 moles) was added. The reaction mixture was stirred and refluxed for 4.5 hours. The progress of the reaction was monitored by HPLC using a Waters Nova-Pak C18 column (3.9X 150mm, particle size 4 μm, UV wavelength 240nm, retention time 3.64 min) and acetonitrile in a volume ratio of 20: 80 and 0.1% phosphoric acid waterThe solution mixture was used as a bank wash at a flow rate of 1 ml/min. After cooling to room temperature, the reaction mixture was filtered to give a yellow solid, which was then washed with acetonitrile (6.5L). The yellow solid was dried in air and then dried in a vacuum oven at 60 ℃ and a pressure < 1mm to give 1760g (88%) of product. The purity of the product determined by HPLC was 99.57%, using a Waters Nova-Pak C18 column (3.9X 150mm, particle size 4 μm, UV wavelength 240nm, retention time 3.64 min) and a mixture of acetonitrile and 0.1% aqueous phosphoric acid in a volume ratio of 20: 80 as the wash liquid at a flow rate of 1 ml/min. The product is in DMSO-d₆For middle use¹H NMR spectrum characterization, exhibiting the following chemical shifts (, ppm): 11.10(s, 1H), 7.47(t, J ═ 7.9Hz, 1H), 7.03 to 6.99(dd, J ═ 4.8 and 8.4Hz, 2H), 6.52(s, 2H), 5.09 to 5.02(dd, J ═ 5.3 and 12.4Hz, 1H), 2.96 to 2.82(m, 1H), 2.62 to 2.46(m, 2H), 2.07 to 2.00(m, 1H); and use of¹³C NMR characterization, exhibiting the following chemical shifts (, ppm): 172.82, 170.11, 168.57, 167.37, 146.71, 135.46, 131.99, 121.70, 110.97, 108.52, 48.47, 30.97, 22.14. The melting point of the product is 315.5-317.5 ℃. Elemental analysis gave the following weight percent results: c, 56.98; h, 3.86; n, 15.35; it is with C₁₃H₁₁N₃O₄The calculated weight percentages are equivalent to: c, 57.14; h, 4.06; n, 15.38.

Example 4 preparation of 3-Nitro-N-ethoxycarbonylphthalimide according to scheme D

Ethyl chloroformate (1.89g, 19.7mmol) was added dropwise over 10 minutes to a stirred solution of 3-nitrophthalimide (3.0g, 15.6mmol) and triethylamine (1.78g, 17.6mmol) in DMF (20mL) at about 0-5 deg.C under a nitrogen atmosphere. The reaction was allowed to return to room temperature and stirred for 4 hours. The reaction mixture was slowly added to a stirred ice-water mixture (60 mL). The slurry was filtered from CHCl₃The solid crystallized from petroleum ether (15mL) and petroleum ether (15mL) to give 3.1g (75%) of the product as an off-white solid: the melting point is 100.0-100.5 ℃;¹H NMR(CDCl₃)8.25(d，J＝7.5Hz，1H)，8.20(d，J＝8.0Hz，1H)，8.03(t，J＝7.9Hz，1H)，4.49(q，J＝7.1Hz，2H)，1.44(t，J＝7.2Hz，3H)；¹³C NMR(CDCl₃)161.45, 158.40, 147.52, 145.65, 136.60, 132.93, 129.65, 128.01, 122.54, 64.64, 13.92; HPLC, Waters Nova-Pak/C18, 3.9X 150mm, 4 micron, 1 ml/min, 240nm, 30/70 CH₃CN/0.1％H₃PO₄(aq), 5.17 min (98.11%); c₁₁H₈N₂O₆Calculated analysis value of (a): c, 50.00; h, 3.05; n, 10.60; measurement values: c, 50.13; h, 2.96; n, 10.54.

EXAMPLE 5 preparation of tert-butyl N- (3-nitrophthaloyl) -L-glutamine

A mixture of the compound from example 4 (1.0g, 3.8mmol), L-glutamine tert-butyl ester acid (0.9g, 3.8mmol) and triethylamine (0.54g, 5.3mmol) in THF (30mL) was refluxed for 24 hours. The THF solvent was removed in vacuo and the residue was dissolved in CH₂Cl₂(50 mL). CH (CH)₂Cl₂The solution was washed with water (2X 15mL) and brine (15mL) and then dried. Removing the solvent, subjecting the residue to flash Chromatography (CH)₂Cl₂EtOAc/7: 3) to yield 0.9g (63%) of a glassy material:¹H NMR(CDCl₃)8.15(d, J ═ 7.9Hz, 2H), 7.94(t, J ═ 7.8Hz, 1H), 5.57(b, 2H), 4.84(dd, J ═ 5.1 and 9.7Hz, 1H), 2.53-2.30(m, 4H), 1.43(s, 9H); HPLC, Waters Nova-Pak/C18, 3.9X 150mm, 4 micron, 1 ml/min, 240nm, 30/70 CH₃CN/0.1％H₃PO₄(aq), 6.48 min (99.68%); chiral analysis, Daicel Chiral Pak AD, 0.4X 25cm, 1 ml/min, 240nm, 5.32 min (99.39%); c₁₇H₁₉N₃O₇Calculated analytical values: c, 54.11; h, 5.08; n, 11.14; measured value: c, 54.21; h, 5.08; n, 10.85.

EXAMPLE 6 preparation of N- (3-Nitrophthaloyl) -L-glutamine

Hydrogen chloride gas was added to CH of the compound (5.7g, 15.1mmol) of example 5₂Cl₂(100mL) the cold solution was stirred (5 ℃ C.) and bubbled for 25 minutes. The mixture was then stirred at room temperature for 16 hours. Diethyl ether (50mL) was added and the resulting mixture was stirred for 30 minutes. The slurry was filtered to give 4.5g of a solid, which was used for the next reaction:¹H NMR(DMSO-d₆)8.36(dd, J ═ 0.8 and 8.0Hz, 1H), 8.24(dd, J ═ 0.8 and 7.5Hz, 1H), 8.11(t, J ═ 7.9Hz, 1H), 7.19(b, 1H), 6.72(b, 1H), 4.80(dd, J ═ 3.5 and 8.8Hz, 1H), 2.30-2.10(m, 4H).

EXAMPLE 7 preparation of (S) -3- (3' -Nitrophthalimido) -piperidine-2, 6-dione

The compound from example 6 (4.3g, 13.4mmol) in anhydrous CH₂Cl₂The suspension mixture (170mL) was cooled to-40 ℃ with an isopropyl alcohol (IPA)/dry ice bath. Thionyl chloride (1.03mL, 14.5mmol) was added dropwise followed by pyridine (1.17mL, 14.5 mmol). After 30 minutes triethylamine (2.06mL, 14.8mmol) was added and the mixture was stirred at about-30 to-40 ℃ for 3 hours. Filtering the mixture with CH₂Cl₂Washing gave 2.3g (57%) of the crude product. The crude product was recrystallized from acetone (300mL) to give 2g of the product as a white solid: melting point 259.0-284.0 deg.C (dec.);¹H NMR(DMSO-d₆)11.19(s, 1H), 8.34(d, J ═ 7.8Hz, 1H), 8.23(d, J ═ 7.1Hz, 1H), 8.12(t, J ═ 7.8Hz, 1H), 5.25-5.17(dd, J ═ 5.2 and 12.7Hz, 1H), 2.97-2.82(m, 1H), 2.64-2.44(m, 2H), 2.08-2.05(m, 1H);¹³C NMR(DMSO-d₆)172.67, 169.46, 165.15, 162.50, 144.42, 136.78, 132.99, 128.84, 127.27, 122.53, 49.41, 30.84, 21.71; HPLC, Waters Nova-Pak/C18, 3.9X 150mm, 4 micron, 1 ml/min, 240nm, 10/90CH₃CN/0.1％H₃PO₄(aq), 4.27 min (99.63%); c₁₃H₉N₃O₆Calculated analytical values: c, 51.49; h, 2.99; n, 13.86; measured value: c, 51.67; h, 2.93; n, 13.57.

EXAMPLE 8 preparation of (S) -3- (3' -Aminophthalimido) -piperidine-2, 6-dione

A mixture of (S) -3- (3' -nitrophthalimido) -piperidine-2, 6-dione (0.76g, 2.5mmol) and 10% Pd/C (0.3g) in acetone (200mL) was hydrogenated at 50psi in a Parr-Shaker apparatus for 24 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The solid was stirred in hot ethyl acetate for 30 minutes to give 0.47g (69%) of the product as a yellow solid: melting point 309-310 ℃;¹HNMR(DMSOd₆)11.10(s, 1H), 7.47(dd, J ═ 7.2 and 8.3Hz, 1H), 7.04-6.99(dd, J ═ 6.9 and 8.3Hz, 2H), 6.53(s, 2H), 5.09-5.02(dd, J ═ 5.3 and 12.4Hz, 1H), 2.96-2.82(m, 1H), 2.62-2.46(m, 2H), 2.09-1.99(m, 1H);¹³C NMR(DMSOd₆)172.80, 170.10, 168.57, 167.36, 146.71, 135.44, 131.98, 121.69, 110.98, 108.54, 48.48, 30.97, 22.15; HPLC, Waters Nova-Pak/C18, 3.9X 150mm, 4 micron, 1 ml/min, 240nm, 15/85 CH₃CN/0.1％H₃PO₄(aq), 4.99 min (98.77%); chiral analysis, Daicel Chiral Pak AD, 0.46X 25cm, 1 ml/min, 240nm, 30/70 hexane/IPA 9.55 min (1.32%), 12.55 min (97.66%); c₁₃H_nN₃O₄Calculated analytical values: c, 57.14; h, 4.06; n, 15.38; measured value: c, 57.15; h, 4.15; n, 14.99.

EXAMPLE 9 preparation of tert-butyl N- (3-nitrophthaloyl) -D-glutamine

The compound of example 4 (5.9g, 22.3mmol), D-glutamine tert-butyl ether (4.5g, 22.3mmol) and triethylamine (0.9g,8.9mmol) of THF (100mL) was refluxed for 24 hours. By CH₂Cl₂The mixture was diluted (100mL) and washed with water (2X 50mL) and brine (50mL), then dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (2% CH)₃CH of OH₂Cl₂) Purification, 6.26g (75%) of glassy product are obtained:¹H NMR(CDCl₃)8.12(d, J ═ 7.5Hz, 2H), 7.94(dd, J ═ 7.9 and 9.1Hz, 1H), 5.50(b, 1H), 5.41(b, 1H), 4.85(dd, J ═ 5.1 and 9.8Hz, 1H), 2.61-2.50(m, 2H), 2.35-2.27(m, 2H), 1.44(s, 9H);¹³C NMR(CDCl₃)173.77, 167.06, 165.25, 162.51, 145.07, 135.56, 133.78, 128.72, 127.27, 123.45, 83.23, 53.18, 32.27, 27.79, 24.42; HPLC, Waters Nova-Pak/C18, 3.9X 150mm, 4 micron, 1 ml/min, 240nm, 25/75 CH₃CN/0.1％H₃PO₄(aq) 4.32 min (99.74%); chiral analysis, Daicel Chiral Pak AD, 0.46X 25cm, 1 ml/min, 240nm, 55/45 hexane/IPA 5.88 min (99.68%); c₁₇H₁₉N₃O₇Calculated analytical values: c, 54.11; h, 5.08; n, 11.14; measured value: c, 54.25; h, 5.12; n, 10.85.

EXAMPLE 10 preparation of N- (3-Nitrophthaloyl) -D-glutamine

Hydrogen chloride gas was added to CH of the compound (5.9g, 15.6mmol) of example 9₂Cl₂(100mL) the cold solution was stirred (5 ℃ C.) with bubbling for 1 hour, then stirred at room temperature for another 1 hour. Ether (100mL) was added and the mixture was stirred for 30 minutes. The mixture was filtered, washed with ether (60mL), and dried (40 ℃, < 1mm Hg) to give 4.7g (94%) of product:¹H NMR(DMSO-d₆)8.33(d, J ═ 7.8Hz, 1H), 8.22(d, J ═ 7.2Hz, 1H), 8.11(t, J ═ 7.8Hz, 1H), 7.19(b, 1H), 6.72(b, 1H), 4.81(dd, J ═ 4.6 and 9.7Hz, 1H), 2.39-2.12(m, 4H);¹³C NMR(DMSO-d₆)173.21、169.99、165.41、162.73、144.45、136.68、132.98、128.80、127.23、122.52、51.87、31.31、23.87。

EXAMPLE 11 preparation of (R) -3- (3' -Nitrophthalimido) -piperidine-2, 6-dione

Anhydrous CH of the compound from example 10 (4.3g, 13.4mmol) was placed in an IPA/dry ice bath₂Cl₂The suspension mixture (170mL) was cooled to-40 ℃. Thionyl chloride (1.7g, 14.5mmol) was added dropwise followed by pyridine (1.2g, 14.5 mmol). After 30 min triethylamine (1.5g, 14.8mmol) was added and the mixture was stirred at-30 to-40 ℃ for 3 h. Filtering the mixture with CH₂Cl₂Washed (50mL) and dried (60 ℃ C., < 1mm Hg) to give 2.93g of product. An additional 0.6g of product was obtained from the dichloromethane filtrate. The two fractions (3.53g) were combined and recrystallized from acetone (450mL) to yield 2.89g (71%) of the product as a white solid: the melting point is 256.5-257.5 ℃;¹H NMR(DMSO-d₆)11.18(s, 1H), 8.34(dd, J ═ 0.8 and 7.9Hz, 1H), 8.23(dd, J ═ 0.8 and 7.5Hz, 1H), 8.12(t, J ═ 7.8Hz, 1H), 5.22(dd, J ═ 5.3 and 12.8Hz, 1H), 2.97-2.82(m, 1H), 2.64-2.47(m, 2H), 2.13-2.04(m, 1H);¹³C NMR(DMSO-d₆)172.66, 169.44, 165.14, 162.48, 144.41, 136.76, 132.98, 128.83, 127.25, 122.52, 49.41, 30.83, 21.70; HPLC, Waters Nova-Pak/C18, 3.9X 150mm, 4 micron, 1 ml/min, 240nm, 10/90CH₃CN/0.1％H₃PO₄(aqueous) 3.35 min (100%); c₁₃H₉N₃O₆Calculated analytical values: c, 51.49; h, 2.99; n.13.86; measured value: c, 51.55; h, 2.82; and N, 13.48.

EXAMPLE 12 preparation of (R) -3- (3' -Aminophthalimido) -piperidine-2, 6-dione

A mixture of the compound from example 11 (1.0g, 3.3mmol) and 10% Pd/C (0.2g) in acetone (250mL) was hydrogenated at 50psi in a Parr-Shaker apparatus for 4 hours. Filtering and mixing with diatomiteThe filtrate was concentrated in vacuo. The yellow solid was slurried in hot ethyl acetate (20mL) for 30 minutes to give 0.53g (59%) of the product as a yellow solid: melting point is 307.5-309.5 ℃;¹H NMR(DMSO-d₆)11.06(s, 1H), 7.47(dd, J ═ 7.0 and 8.4Hz, 1H), 7.02(dd, J ═ 4.6 and 8.4Hz, 2H), 6.53(s, 2H), 5.07(dd, 1 ═ 5.4 and 12.5Hz, 1H), 2.95-2.84(m, 1H), 2.62-2.46(m, 2H), 2.09-1.99(m, 1H);¹³C NMR(DMSO-d₆)172.78, 170.08, 168.56, 167.35, 146.70, 135.43, 131.98, 121.68, 110.95, 108.53, 48.47, 30.96, 22.14; HPLC, WatersNove-Pak/C18, 3.9X 150mm, 4 microns, 1 ml/min, 240nm, 10/90CH₃CN/0.1％H₃PO₄(aq), 3.67 min (99.68%); chiral analysis, Daicel Chiral Pak AD, 0.46X 25cm, 1 ml/min, 240nm, 30/70 hexane/IPA 7.88 min (97.48%); c₁₃H_nN₃O₄Calculated analytical values: c, 57.14; h, 4.06; n, 15.38; measured value: c, 57.34; h, 3.91; n, 15.14.

Example 13 preparation of 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione according to scheme E

A mixture of 3-aminophthalic acid hydrochloride (200g, 0.92mol, available from Prosynth, Suffolk, UK), 3-aminoglutarimide hydrochloride (159g, 0.96mol, available from Evotec OAI, Hamburg, Germany), acetonitrile (2.0L) and acetic acid (577g, 9.6mol, available from Fisher scientific) was charged to the reactor. After stirring the mixture for 15 minutes, triethylamine (465.0g, 4.6mol, obtained from Aldrich, Milwaukee, Wis.) was added dropwise over 30-35 minutes while the reaction temperature was maintained at 20-25 ℃. The reaction mixture was then stirred for a further 10-15 minutes and then refluxed at about 85-87 ℃ for about 5-7 hours or until in-process control (i.e., HPLC AP at 240 nm) indicated that < 2% of the 3-aminophthalic acid remained in the reaction mixture. The reaction mixture was cooled to about 20-25 ℃ over 1-2 hours and 1.0L of water was added over 15-30 minutes at about 20-25 ℃. The resulting mixture was stirred at about 15-20 ℃ for about 20-30 minutes to give a yellow solid precipitate, which was filtered, washed with DI water (3 × 1.0L) and acetonitrile (2 × 500mL), and then dried under vacuum at about 35-40 ℃ to a constant weight of 210.0g (84%).

Example 144 preparation of amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione

The compound of example 14 was prepared similarly according to the procedure of example 13, except that: acetic acid is absent; the amount of triethylamine was reduced from 4.6 moles to 3.2 moles; the reflux time was increased from about 5-7 hours to about 47 hours. The amount of 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione in the reaction mixture was 94%.

Example 154 preparation of amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione

The compound of example 15 was prepared similarly according to the procedure of example 13, except that: there was no acetic acid and 9.2 moles of imidazole were substituted for 4.6 moles of triethylamine. The amount of 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione in the reaction mixture was 92%.

Example 164 preparation of amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione

The compound of example 16 was prepared similarly according to the procedure of example 13, except that: 4.6 moles of triethylamine were replaced with 9.2 moles of imidazole. The amount of 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione in the reaction mixture was 85%.

Example 174 recrystallization of amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione

Racemates and stereoisomers of 4-amino-2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione, such as the compounds of examples 3, 8 and 12-16, can be purified by recrystallization as described below. A mixture of the crude product from example 13 (200g) and DMSO (800mL) was charged to the reactor. The resulting slurry was heated to about 45-50 ℃ and then stirred until complete dissolution of the solids was achieved (about 10-15 minutes). The resulting solution was clarified at about 45-50 ℃ and then rinsed with DMSO (400mL) at about 45-50 ℃. The solution was added to purified water (7.2L) at about 75-80 deg.C for at least 60 minutes. The resulting suspension is cooled to about 15-20 c over at least 1.5 hours and stirred at the same temperature for about 1.5-2 hours. The suspension was filtered and the solid was washed with purified water (2X 2L). The purified product was dried under vacuum at about 35-40 ℃ until constant weight was achieved. The yield of the purified product was 196.8g (98% recovery). The melting point of the purified product was 321-.

The scope of the invention is not to be limited by the specific embodiments disclosed in the examples, which are intended as illustrations of some aspects of the invention, and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims (29)

1. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof,

comprising the step of cyclizing a compound of formula (II) or formula (IIA), or a salt thereof, with a cyclizing agent of formula (V) in a solvent,

wherein R is¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) An alkynyl group; x and Y are each independently an unsubstituted or substituted imidazolyl, benzimidazolyl, or benzotriazolyl, wherein the solvent is selected from the group consisting of acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, and combinations thereof.

2. The method of claim 1, wherein the compound of formula (II) is cyclized.

3. A process according to claim 1, wherein the compound of formula (IIA) is cyclized.

4. The method of claim 1, wherein the compound of formula (I) is a solvate, which is a hydrate.

5. The process of claim 1 wherein the cyclizing reagent is a carbonyldiimidazole compound.

6. The method of claim 5, wherein the carbonyldiimidazole compound is 1, 1' -carbonyldiimidazole.

7. The process of claim 6, wherein the ratio of the compound of formula (II) or formula (IIA) to 1, 1' -carbonyldiimidazole is 1: 1 to 1: 1.2.

8. the process of claim 1 wherein the solvent is acetonitrile or N-methylpyrrolidone.

9. The process of claim 8 wherein the solvent is acetonitrile and the reaction temperature is from 80 ℃ to 87 ℃.

10. The method of claim 9, wherein the reaction time is from 1 hour to 5 hours.

11. The process of claim 1, wherein the compound of formula (II) or formula (IIA) is prepared by reducing the compound of formula (III) or formula (IIIA), respectively, with a reducing agent:

wherein R is¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl.

12. The method of claim 11, wherein the reducing agent is hydrogen and 10% Pd/C.

13. The method of claim 12, wherein the hydrogen pressure is from 2.76 bar to 3.45 bar.

14. The method of claim 12, wherein the reaction is carried out in a solvent.

15. The method of claim 14, wherein the solvent is methanol.

16. The process of claim 11 wherein the compound of formula (III) or (IIIA) is prepared by reacting 3-nitrophthalic anhydride with a compound of formula (IV) or (IVA), respectively:

wherein R is¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl.

17. The process of claim 16, wherein the reaction is carried out in a solvent.

18. The method of claim 17 wherein the solvent is dimethylformamide.

19. The process of claim 17, wherein the reaction temperature is from 80 ℃ to 87 ℃.

20. The method of claim 1, wherein the compound of formula (I) is a free amine.

21. The method of claim 20, further comprising a molar ratio of 1: 1 with an acid to form an acid salt.

22. The method of claim 21, wherein the acid is hydrochloric acid.

23. The process of claim 11, wherein the compound of formula (III) is prepared by:

(a) reacting 3-nitro-N-ethoxycarbonyl-phthalimide with a glutamine ester of formula (VIII) or an acid salt thereof in the presence of a first catalyst,

forming a compound of formula (IX), or a salt, solvate, polymorph or stereoisomer thereof; and

(b) reacting a compound of formula (IX), or a salt, solvate, polymorph or stereoisomer thereof, with hydrogen chloride, wherein R¹Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) Alkynyl radical, R⁸Is alkyl or aralkyl.

24. The method of claim 23, further comprising the step of preparing 3-nitro-N-ethoxycarbonyl-phthalimide by reaction of 3-nitrophthalimide and ethyl chloroformate in the presence of a second catalyst.

25. The method of claim 24, wherein the first catalyst and the second catalyst are each triethylamine.

26. The method of claim 25, wherein R is¹Is H, R⁸Is tert-butyl or benzyl.

27. The method according to claim 26, wherein the compound of formula (VIII) is L-glutamine tert-butyl ester hydrochloride and the compound of formula (III) is the (S) -enantiomer.

28. The method according to claim 26, wherein the compound of formula (VIII) is D-glutamine tert-butyl ester hydrochloride and the compound of formula (III) is the (R) -enantiomer.

29. The process according to claim 26, wherein the compound of formula (VIII) is a racemic mixture of glutamine tert-butyl ester hydrochloride and the compound of formula (III) is a racemic mixture.