BRPI0803966A2 - process of preparation of highly optical pure carvedilol - Google Patents

Abstract

Process of preparing highly optical pure carvodilol. The present invention relates to a process for the efficient preparation of highly optical pure chiral carvedilol. According to the present invention, a chiral oxazolidine-2-one or oxazolidine-2-thion having formula 2, produced from the reaction of 2- (2-methoxyphenoxy) ethylamine N-protected with a chiral glycidol derivative is used as a essential intermediate for the preparation of chiral carvedilol. Specifically, the process for preparing chiral carvedilol comprises a) reacting a compound of formula 2 with a halogenating agent, a sulfonating agent or a mitsunobu reagent to activate a hydroxyl group of the compound of formula 2, followed by a nucleophilic substitution reaction with 9H-4-hydroxy carbazole to produce a compound of formula 7; and b) submitting the compound of formula 7 obtained to a deprotection reaction in the presence of an inorganic base to produce the target chiral carvedilol. The process according to the present invention can be carried out in a mild condition. The process also does not require any purification procedure extraordinary, nor does it involve reduction in optical purity. Consequently, the process according to the present invention produces highly optical pure chiral carvedilol in a simple and efficient way.

Description

Process of preparation of highly optical pure carvedilol.

The present invention relates to a carvedilol preparation process. More specifically, the present invention relates to an efficient chiral carvedilol preparation process.

Background of the Invention

Most recently developed and commercially available drugs are chiral products. This is attributed to side effects or reduced efficacy caused by racemic drugs. Consequently, in order to increase safety and efficacy, studies to develop chiral drugs that contain optically pure stereoisomers have been widely sought. In chiral drugs, chemical high purity and high optical purity are necessary to ensure safety and efficacy.

Carvedylol (IUPAC NAME: 1- (9H-carbazol-4-yloxy) -3 - [[2- (2-methoxyphenoxy) ethyl] amino] -2-propanol) is a compound having the formula 1:

<formula> formula see original document page 2 </formula>

where * represents a chiral center.

As shown in formula 1, carvedilol has a chiral center and may exist in either (R) or (S) isomer. At this point, as an α-adrenoreceptor blocker, isomer (R) and isomer (S) exhibit almost the same activities. In contrast, as a prenatal receptor blocker, (S) isomer exhibits improved superior activity over (R) isomer (EP 127,099; Chirality 1989, 1, 265; J. Pharm. Exp. Ther., 1992, 263, 92; Clin Pharmacokin., 1994, 26,335; Cardiovasc. Res., 1994, 28, 400; J. of Chromatography B. 1996, 682, 349). In addition, carvedilol is now used as an antioxidant, anti-inflammatory agent, anti-apototic agent (The American Journal of Cardiologyl 2004, 93 (9A), 3B). For these reasons, providing an efficient and highly efficient process of preparing pure chiral carvedilol in an economical manner is an important task for the development of various drugs comprising chiral carvedilol.

Conventional processes for preparing carvedilol chiral are shown in reaction scheme 1:

Reaction Scheme 1 <formula> formula see original document page 3 </formula>

wherein R represents hydrogen or a benzyl group.

As shown in reaction scheme 1, target ocarvedilol was prepared from a ring opening of an epoxy carbazole carboxylic acid of formula 3 with an ethylamine compound of formula 4 (R = hydrogen, U.S. Patent Nos. 4,503,067 and 4,697 .022). However, the process generates deformation of a bi-substituted byproduct that is not easy to remove during the purification procedure. The process requires an extraordinary purification procedure in order to delay the preparation of highly optical pure carvedilol. In addition, the loss of target carvedilol is inevitable in the purification procedure, resulting in a significant reduction in carvedilol yield.

In order to avoid the resulting disadvantage of the bi-substituted product, further attempts have been made. In order to prevent formation of the bisubstituted product, an N-protected compound of formula 4 (R = benzyl) was used as the primary material in reaction scheme 1 and applied to the ring opening of the chiral epoxy compound of formula 3 (R = benzyl, EP 918,055). The process does not generate bi-substituted product. It has the disadvantage, however, that an expensive palladium catalyst must be used in order to unprotect the benzyl group.

As an alternative, the ethylamine compound of formula 4 was used excessively over the compound of formula 3 to reduce the formation of the displaced by-product (R = hydrogen, WO 02/00216). Although the process could reduce the formation of bi-substituted by-product, problems still remain caused by the small amount of bi-substituted product. In addition, the product suffered low price competitiveness due to overuse of the high cost ethylamine compound.

In addition, the ethylamine compound of formula 4 or its benzylated form is degraded by exposure to light and air. Consequently, the compound of formula 4 has limitations for application in mass production. In order to overcome this disadvantage, the acid addition salt of the formula 4 deethylamine compound (R = H) was used as the primary material in the ring-opening reaction with the compound of formula 3 to increase stability (WO 2004/041783). The process has an applicable advantage in the mass production of chiral carvedilol. Nevertheless, it has suffered from the formation of the displaced byproduct and the overuse of the ethylamine compound. In order to avoid the formation of the displaced byproduct, further attempts have been tried.

The amino group of the compound of formula 4 was first protected with a benzyl group and a chloro-propanoyl group was introduced. The product obtained was alkylated with an epoxycarbazole of formula 8, followed by a deduction step and a debenzylation step to produce carvedilol (Korean Patent Publication No. 2005-0003764). However, the process requires a fortetal reducing agent such as sodium borohydride or lithium borohydride and an expensive palladium catalyst.

Yet another process of preparing carvedilol known in the art comprises reacting the amino compound of formula 4 with a compound carbonate to produce a carbamate containing two residual groups, followed by a cyclization reaction to produce an oxazolidinone compound which is used as an intermediate for synthesis. of carvedilol (EP 1,282,601 and 1,367,052). In the process, the oxazolidinone compound was alkylated with 9 H-4-hydroxycarbazole and unprotected to produce carvedilol.

Although the above two processes effectively inhibit formation of the bi-substituted byproduct, they are not suitable for chiral decarvedilol production.

As mentioned above, conventional methods presented one or more unresolved technical problems for the application in mass production of highly optical pure chiral carvedilol. Accordingly, an efficient process of preparing highly optical pure chiral carvedilol is now urgently needed.

According to the extensive studies of our inventors, the efficient preparation of the highly optical pure principal intermediate and the provision of efficient chemical synthesis pathways that are fundamental in the efficient mass production of chiral carvedilol have been found.

As a result of the in-depth studies of our inventors, a chiral carvedilol preparation process is provided, wherein a chiral oxazolidinine having formula 2 is used as the primary intermediate. The major intermediate of formula 2 can be synthesized efficiently by the provision of highly optical pure chiral glycidol derivative with N-protected 2- (2-methoxyphenoxy) ethylamine, both of which are commercially available and mass-produced industrially.

Formula 2 <formula> formula see original document page 5 </formula>

where * represents a chiral center and X represents oxygen or sulfur.

The preparation of chiral carvedilol from the main intermediate of formula 2 comprises a) reacting a compound of formula 2 with a halogenating agent, a sulfonating agent or a mitsunobu reagent to activate a hydroxyl group of the compound of formula 2, followed by the nucleophilic substitution reaction with 9H-4-hydroxy carbazole to yield a compound of formula 7; and b) subjecting the obtained formula 7 compound to a deprotection reaction in the presence of an inorganic base to produce the target chiral carvedilol.

Specifically, the compound of formula 2 is prepared from a ring opening reaction and the subsequent in situ intramolecular cyclization reaction between an amino compound of formula 4 and a chiral glycidol of formula 5, followed by the deprotection reaction and then the chiral carvedilol with high optical purity is produced from the compound of formula 2. At this point, the amino compound of formula 4 effectively prohibits formation of the displaced by-product and produces an oxazolidin-2-one or oxazolidin-2-thione of formula 2 by of a ring-opening reaction with the compound of formula 5 and the subsequent intramolecular cyclization reaction in situ. Thereafter, the hydroxyl group of the compound of formula 2 obtained in this form is activated with the aid of a halogenating agent, a desulfonating agent or a mitsunobu reagent and undergoes nucleophilic substitution reaction with 9H-4-hydroxy carbazole to produce the compound of formula 7 ( 5- (9H-carbazol-4-yloxymethyl) -3- [2- (2-methoxy-phenoxy) -ethyl] -oxazolidin-2-one or (5- (9H-carbazol-4-yloxymethyl) -3- [ 2 [(2-Methoxy-phenoxy) -ethyl] -oxazolidin-2-thione) The compound of formula 7 has open rings in the presence of an inorganic base to produce the chiral carvedilol of formula 1.

The process according to the present invention is safe and industrially applicable, and provides chiral carvedilol in a pure highlyotic form.

Detailed Description of the Invention

The present invention relates to the efficient chiral carvedilol preparation process which comprises a) reacting a compound of formula 2 with a halogenating agent, a sulfonating agent or a mitsunobup reagent to activate a hydroxyl group of the compound of formula 2 followed by nucleophilic disubstitution reaction with 9H-4-hydroxycarbazole to yield a compound of formula 7; and b) subjecting the compound of formula 7 obtained to a protective reaction in the presence of an inorganic base to produce the target chiral carvedilol. The process is summarized in reaction scheme 2:

Reaction Scheme 2

<formula> formula see original document page 6 </formula>

In reaction scheme 2, * represents a chiral center and X represents oxygen or sulfur.

As shown in reaction scheme 2, the present invention utilizes, as chiral base intermediate, chiral oxazolidin-2-one or oxazolidin-2-thione having the formula 2, wherein the nitrogen atom is substituted with a 2- (2- methoxy-phenoxy) ethyl.

The base intermediate is prepared by opening the rings of a chiral glycidol compound of formula 5 by an amino compound of formula 4 and subsequent intramolecular cyclization in situ, followed by hydroxy deprotection of a compound of formula 6.

A specific example of the amino compound of formula 4 used in the preparation of the base chiral intermediate of formula 2 is as follows:

Formula 4

<formula> formula see original document page 6 </formula>

where X represents oxygen or sulfur, and Y represents

a residual group.

The compound of formula 4 may be produced in a known procedure using a corresponding primary amino compound. Particularly when X is an oxygen atom, it may be produced by deriving the primary amino compound with a carboxylic acid, a carboxylic acid ester, a carbonyl halide compound, a carboxylic acid anhydride or haloformate.

When X is a sulfur atom, the compound of formula 4 may be produced by reacting the primary amine compound with a thiocarboxylic acid ester (J. Chem. Soc., 1989, 2631; Chem. Ber. 1971, 104, 3146) or its corresponding isothiocyanate (Chem. Ber. 1914, 47, 1255; J. Am. Chem. Soc., 1968, 90,6008; J. Chem. Eng. Date, 1980, 25, 176). Preferred examples of the residual group Y are C 1 -C 10 alkoxy group, C 6 -C 10 aryloxy aryloxy group, allyloxy group, C 7 -C 14 alkylaryl group.

A specific example of the chiral glycidol compound of formula 5 used in the preparation of the chiral base intermediate of formula 2 is as follows:

Formula 5

<formula> formula see original document page 7 </formula>

In formula 5, * represents a chiral center and R1 represents a hydroxy protecting group. Preferred examples of R1 include C1-C10 alkyl group, C2-C10 alkenyl group, C2-C10 alkynyl group, C1-C10 alkoxy group, C1-C10 alkyloxycarbonyl group, C6-C10 aryl group, C3-C10 cycloalkyl group, C4-C10, heterocycle or polycyclic group, C2-C10 carbonyl group, C2-C10 carboxyl group, silyl group, ether group, thioether group, selenoether group, ketone group, aldehyde group, ester group, grupophosphoryl group, phosphonate group, sulfonyl group or - (CH2) k-R2 (wherein R2 represents C2-C10 alkenyl group, C2-C10 alkynyl group, C1-C10 alkoxy group, C1-C10 alkyloxycarbonyl group, C6-C10 aryl group, C3-C10 cycloalkyl group, grupocycloalkenyl group C4-C10, heterocycle or polycyclic group, C2-C10 carbonyl group, C2-C10 group carboxyl, silyl group, ether group, thioether group, selenoether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group, sulfonyl group (an integer from 1 to 8).

The chiral glycidol of formula 5 is commercially available and can be readily produced from a known procedure. Specifically, chiral glycidol may be prepared from an asymmetric allyl alcohol epoxidation reaction (U.S. Patent Nos. 4,946,974, 5,153,388 and 5,344,947) of 3-chloro-propanediol (JP 7-165743, US). 5,965,753 and 2,248,635 and DE 1,226,554), or from an asymmetric catalytic reaction using enzyme or metal catalyst (J. Am.Chem. Soc. 1984, 106, 7250; Tetraedron Asymetry 1991, 2, 481; Enzyme Microb.Technoi 1991, 13, 306; Biotech. Tech., 1998, 12, 225; Tetrahedron 1994, 40, 8885; Biotech. Bioeng, 1996, 49, 70; Acta Chem. Scand. 1996, 50, 249; TetrahedronAsymmetry 1997 , 8, 639; Biotech, Tech, 1998, 12, 225; US 6,720,434; WO 01/89690; JP2003-534117; EP 289.655; US 2004-0054201; JP 2004-515356; WO 02/48162, KR 2002- 01219; US 6,262,278; US 6,448,414; US 6,693,236; US 6,800,766; and WO 00/09436).

Preparation of chiral oxazolidin-2-one or oxazolidin-2-thione formula 2, the base intermediate for the synthesis of chiral carvedilol, from the compound of formula 4 and the compound of formula 5 is summarized in reaction scheme 3:

Reaction Scheme 3

<formula> formula see original document page 8 </formula>

In reaction scheme 3, * represents a chiral center, and X and Y and R1 are the same as defined above.

As shown in reaction scheme 3, Ν-protected compound of formula 4 participates in the chiral glycidol ring-opening of formula 5. As a result, an intermediate represented as formula 9 is produced. The intermediate produced in this way undergoes an intramolecular cyclization reaction in situ to produce hydroxy-protected chiral oxazolidin-2-one or the oxazolidin-2-thione compound of formula 6.

At this point, the compound of formula 5, combined with the compound of formula 4, in an amount of 0.8 to 5 equivalents, preferably 1 to 1.5 equivalents, is added. The ring opening reaction and the subsequent in situ intramolecular decyclization reaction are conducted in the presence of a base. The base to be used includes inorganic or organic bases. For example, an alkali metal salt such as sodium methoxide, lithium methoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, an imidazole, 2-6-lutidine, Ν, Ν- Dimethylamino pyridine and its salts, tertiary amine and hydrated form may be used as a base. The organic solvent to be used is not particularly limited. Ν, Ν-dimethylformamide, an aliphatic or aromatic hydrocarbon solvent, a halogenated hydrocarbon, and ether may be used as organic solvents. Specifically, an aromatic organic solvent such as toluene or benzene, a haloalkane such as dichloromethane or chloroform or an ether such as ethyl ether, tetrahydrofuran or dioxane may be used. The reaction temperature is preferably set within a range of 0 to 150 ° C, more preferably 80 to 100 ° C.

The compound of formula 6 thus obtained is applied to the next deprotection reaction without any extraordinary purification (eg fractional distillation or recrystallization). Specifically, upon complete consumption of the starting materials and intermediates involved in the ring-opening reaction and subsequent in situ intramolecular cyclization reaction, a deprotecting agent of the hydroxy protecting group is added to the same reactor to produce the base chiral intermediate of formula 2 (Protecting Groups). , Thieme Medical Publishers Inc., New York, 1994; Protective Groups in Organic Synthesis, John Wiley and Sons, Inc, 1991).

The compound of formula 2 may also be directly applied, without further purification, to an alkylation reaction with the compound of formula 8. In other words, the hetero ring compound of formula 2 containing a hydroxy group is prepared in a highly pure form so that may be applied directly as a starting material for alkylation and subsequent protective steps for the synthesis of the target carvedilol.

The preparation of a precursor compound of formula 7 from the compound of formula 2 is accomplished by reacting a compound of formula 2 with a halogenating agent, a sulfonating agent or a reagentemitsunobu to activate a hydroxyl group of the compound of formula 2, followed by the reaction of nucleophilic substitution with 9H-4-hydroxy carbazole. This is summarized in Scheme 4, wherein activation by the halogenating agent or sulfonating agent is expressed as process (1) and activation by mitsunobu reagent as process (2):

Reaction Scheme 4

<formula> formula see original document page 9 </formula>

In reaction scheme 4, * represents a chiral center, Z represents a halogen group or a sulfonate group and X, Y and R1 are the same as defined above.

As shown above, the compound of formula 7 may be prepared by subjecting the compound of formula 2 to a halogenation or desulfonation reaction to produce a compound of formula 10, followed by a nucleophilic attack by 9H-4-hydroxy carbazole. Alternatively, it may be prepared by reacting mitsunobu of the compound of formula 2 with 9H-4-hydroxy carbazole.

More specifically, as shown in process (1) of reaction scheme 4, the compound of formula 2 produces a compound of formula 10 by reaction with a halogenating agent. Examples of dehalogenating agents at this point include thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus tribromethode and phosphorus trichloride. The halogenating agent is typically added in an amount of 0.8 to 10 equivalents, preferably 1.1 to 2.0 equivalents.

In addition, the compound of formula 10 may also be prepared by reacting the compound of formula 2 with a sulfonating agent (sulfur halide) by converting the hydroxy group of compound 2 to the corresponding sulfonate groups. Examples of sulfonating agents at this point include methanesulfonyl chloride (abbreviated, MsCl), p-toluenesulfonyl chloride (abbreviated, TsCl), benzenesulfonyl chloride, trifluoromethanesulfonyl chloride (abbreviated TfCl) and nitrobenzenesulfonyl chloride. The sulfonating agent is typically added in an amount of 0.8 to 5 equivalents, preferably from 1.1 to 2.0 equivalents.

The halogenation or sulfonation reaction is conducted in the presence of an inorganic base. As an example of an organic base, an imidazole, 2-6-lutidine, α, β-dimethylamino pyridine and its salts, or tertiary amine and its hydrated form may be mentioned. A trialkylamine including trimethylamine, triethylamine and diisopropylethylamine is preferred. The base is added in an amount of 0.8 to 10 equivalents, preferably 1.0 to 3.0 equivalents. The reaction is conducted in the presence of an organic solvent. Sometimes it can be conducted without any solvents. The organic solvent to be used is not particularly limited. N1N-dimethylformamide, an aliphatic solvent or aromatic hydrocarbon, a halogenated hydrocarbon and an ether may be used as an organic solvent. Specifically, an aromatic organic solvent such as toluene or benzene, a haloalkane such as dichloromethane or chloroform or an ether such as ethyl ether, tetrahydrofuran or dioxan may be used. The reaction temperature is preferably set in the range 0 to 100 ° C, more preferably 0 to 20 ° C.

In the reaction, the compound of formula 10 is produced in highly pure form by a typical preparation procedure. The obtained compound may be subjected directly to the subsequent alkylation reaction without any extraordinary purification. This simplifies the preparation of chiral carvedilol and increases the reaction time.

The compound of formula 10 provides a compound of formula 7, which is a precursor to carvedilol, by reaction with 9H-4-hydroxy carbazole of formula 8. 9H-4-hydroxy carbazole of formula 8 is commercially available or may be mass-produced. by a well known procedure (DE 2,240,599 and US4,273,711).

The specific reaction condition between the compound of formula 10 and 9H-4-hydroxy carbazole of formula 8 is as follows. 9H-4-hydroxy carbazole of formula 8 is added, based on the compound of formula 10, in a range of 0.5 to 2.0 equivalents, preferably 1.0 to 1.1 equivalents. First, the compound of formula 10 and 9H-4-hydroxy carbazole of formula 10 are dissolved in an organic solvent. To the solution, 0.1 to 10 equivalents of a base (preferably 0.5 to 2.0 equivalents) is added. The reaction temperature is adjusted between 30 and 150 ° C, preferably between 70 and 100 ° C. The base to be used includes inorganic or inorganic bases. As an example of inorganic base, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or a metal alkoxide may be mentioned. Potassium carbonate or sodium carbonate is preferable. For the organic base, a trialkylamine, such as trimethylamine, triethylamine or disopropylethylamine compound is preferable. The organic solvent to be used is not particularly limited. Ν, Ν-dimethylformamide, dimethyl sulfoxide, an aliphatic solvent or aromatic hydrocarbon, a halogenated hydrocarbon, an ether or an alcohol may be used as organic solvents. A preferred example of alcohol is C1-C4 alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, or t-butanol.

The obtained compound can be subjected directly to a deprotection reaction in a container without any extraordinary purification. This is due to the fact that the procedure is performed in a very pure manner and that the small amount of impurities can be easily removed by the purification procedure of the subsequent deprotection reaction.

According to the present invention, the compound of formula 7 may also be prepared by directly coupling the compound of formula 2 with 9H-4-hydroxy carbazole of formula 8. This means that the compound of formula 2 may be converted directly to the compound of 7 by coupling with the compound of formula 8, without any procedure for increasing the residual capacity of the halogenation or sulfonation mediated hydroxide group. This procedure is demonstrated as process (2) in reaction scheme 4. As a result of process (2), carvedilol can be produced by reduced steps compared to process (1). The mitsunobu reaction can be applied to the direct coupling of the compound of formula 2 with the compound of formula 8 by process (2) of reaction scheme 4. In the mitsunobu reaction, activation of the hydroxy group of compound 2 and nucleophilic substitution in situ are conducted as a reaction of a vessel ( Advanced Organic Chemistry 3rd Ed. Part B. Plenum Press, 1993; Advanced Organic Chemistry, fourth edition, Wiley-Interscience publication, 1992).

The preparation of the compound of formula 7 by process (2) is explained in detail. The hetero ring compound of formula 2 which contains the hydroxy group is dissolved in an organic solvent, and a mitsunobu reagent comprising a phosphine compound of formula 11 and a dialkyl azocarboxylate of formula 12 is added to activate the hydroxy group. 9H-4-hydroxycarbazole of formula 8 is added to the solution. 9H-4-hydroxycarbazole nucleophilic attack of formula 8 the activated hydroxy group produces the compound of formula 7.

Specific examples of the compound of formula 11 and the compound of formula 12 are as follows:

Formula 11

<formula> formula see original document page 12 </formula>

wherein, R ', R "represent substituents. Preferably, each R', R" and R '"independently represent C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy, C6-C10 aryl group or (CH2) 1 -Rs (wherein R3 represents C3-C6 cycloalkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group or C6-C10 aryl group and L is an integer from 1 to 8).

Formula 12

<formula> formula see original document page 12 </formula>

wherein each AeB independently represents C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group or C2-C6 alkynyl group.

The compound of formula 7 prepared by process (2) of reaction scheme 2 may also be applicable to the subsequent deprotection reaction without any purification procedure as the phosphine oxide produced as a byproduct can be easily removed by the purification procedure. following deprotection reaction. This means that the compound of formula 7 can be applied directly, without any purification, to the deprotection as reaction of a container. This provides process simplicity and increased throughput.

The preparation of carvedilol from the compound of formula 7 is illustrated in reaction scheme 5:

Reaction Scheme 5

<formula> formula see original document page 13 </formula>

As mentioned above, the conversion of the compound of formula 7 to carvedilol is accomplished by adding a base, optionally in combination with a reaction solvent, to the reactor within which the compound of formula 7 is produced as shown in reaction scheme 4. Generally, a compound of oxazolidin-2-one or oxazolidin-2-thione undergoes a hydrolysis reaction in a basic condition to produce an amino alcohol (oxazolidin-2-one hydrolysis: J. Org. Chem., 1986, 51, 713; J Chem., 1988, 53, 3865; Tetrahedron Lett., 1990, 51, 7407; Tetrahedron 1998, 54, 7221; Oxazolidin-2-thione hydrolysis: J. Org. Chem., 1992, 57,433; J. Am. Chem. Soc., 1994, 116, 5607). According to the present invention, the compound of formula 7 was considered applicable to the deprotection reaction to produce carvedilolvo. As shown in reaction scheme 5, after the primary material of reaction scheme 4 has been completely consumed, a base or a combination of a base and a solvent is added to the same stirred reactor to complete deprotection sand. According to the preferred embodiment of the present invention, a stirring base was added to the nucleophilic substitution reaction reaction mixture between the compound of formula 2 and the compound of formula 8, followed by the addition of a solvent such as water, alcohol and a mixture of these. At this point, the temperature temperature is typically in the range of 0 to 150 ° C, preferably 30 to 70 ° C.

The base is added, based on the compound of formula 2, at a concentration of 0.8 to 10 equivalents, preferably 1.0 to 3.0 equivalents. As inorganic bases to be used, inorganic carbonate (such as sodium carbonate, potassium carbonate, decesium carbonate or sodium bicarbonate) or inorganic hydroxide (such as sodium hydroxide, potassium hydroxide or lithium hydroxide) may be mentioned.

As a solvent added in admixture with the base, water, alcohol or mixtures thereof are generally used. A preferred example of the alcohol is C1 -C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or t-butanol.

As mentioned above, the present invention can be distinguished from the prior art by the fact that the target chiral carvedilol of formula 1 is efficiently prepared from the base chiral intermediate of formula 2 in a highly optical purity and mild condition applicable to industrial bulk production. In addition, the base chiral intermediate is prepared, without any change in quality, from the optically pure chiral glycidyl derivative.

On the other hand, according to conventional chiral carvedilol preparation processes as explained in reaction scheme 1, the starting material 4- (2,3-epoxypropyl) carbazole of formula 3 cannot be obtained in a highly optical form. Specifically, the compound of formula 3 is prepared from the nucleophilic substitution of chiral glycidyl m-nitrobenzenesulfonate with 9H-4-hydroxy carbazole of formula 8. Although the reaction has been reported to proceed in a stereoselective manner as if the chiral configuration sidoretide (J. Org. Chem., 1989, 54, 1295; Tetrahedron: Asymmetry 1992, 3, 539), Dubois et al reported that the optical purity of the compound of formula 3 was significantly reduced in some cases (J. Med. Chem., 1996, 39, 3256). Moreover, according to the studies of our inventors, it was concluded that the optical purity of the product is very sensitive to reaction conditions. Consequently, the process is believed to require very strict reaction conditions. As a result, the process is not applicable to mass industrial production.

According to the present invention, the highly optically pure base intermediate of Formula 2 is prepared from the chiralotically pure glycidol derivative without any deterioration of optical purity. In addition, optical purity reduction will not occur in the preparation of chiral carvedilol from the intermediate based on formula 2. Accordingly, the process according to the present invention provides ocarvedilol in a pure highly optical form as compared to conventional forms.

Furthermore, the process according to the present invention requires no extraordinary purification of the intermediate products involved in the preparation of the target chiral carvedilol. This indicates that the process according to the present invention is a simple and economical process. Furthermore, the process according to the present invention is conducted in such a mild condition that it does not require vigorous reaction conditions or a strong reducing or oxidizing agent. As a result, the process according to the present invention is suitable for mass industrial production application.

Conclusively, we have established the process of preparing highly optical pure carvedilol from the chiral compound of formula 2 without any loss of chirality and in an industrially applicable manner.

The present invention will be more fully illustrated below with reference to the examples. It will be understood, however, that these examples are suggested for illustration only and should not be construed as limiting the scope of the present invention. Numerous modifications may be made without departing from the scope and spirit of the present invention.

Examples

Example 1

Preparation of (S) -3- [2- (methoxyphenoxy) ethyl] -5- (hydroxymethyl) oxazolidin-2-one (Formula 2, X = oxygen)

106.9 g of isobutyl 2- (2-methoxyphenoxy) ethylcarbamate (0.4 mol) and 6.40 g of lithium t-butoxide (0.08 mol) were dissolved in N, N-dimethylformamide (200 ml) and stirred at room temperature for ten minutes. To the mixture, 69.5 g (0.44 mol) of (S) -2-oxiranylmethoxytetrahydropyran was added and stirred at 80 ° C for 24 hours. The reaction mixture was cooled to room temperature and adjusted to pH 1 using a 20% sulfuric acid and methyl alcohol solution. The reaction mixture was further stirred at room temperature for five hours and neutralized using triethylamine. To the solution was added water (400 mL) and dichloromethane (1000 mL). After separation of an organic layer from the mixing solution, it was dried with anhydrous magnesium sulfate and filtered. Evaporation under reduced pressure yielded the target compound of formula 2 in its liquid phase. The obtained product was subjected without further purification to the following deprotection reaction.

Yield: 104.6 g (98%).

1 H NMR (300MHz, CDCl 3): δ 2.32 (br s, 1H) 3.65-3.74 (m, 4H), 3.80-3.92 (m, 2H), 3.85 (s, 3H), 4.18 (t, J = 7.8Hz, 2H), 4.60 (m, 1H), 6.89-6.99 (m, 4H).

Example 2

Preparation of (R) -3- [2- (2-Methoxyphenoxy) ethyl] -5- (hydroxymethyl) oxazolidin-2-one (Formula 2, X-oxygen)

Using 53.46 g of isobutyl 2- (2-methoxyphenoxy) ethylcarbamate solution in N, N-dimethylformamide (0.2 mol), 3.20 g of lithium t-butoxide (0.04 mol) and 34, 76 g of (R) -2-oxiranylmethoxy tetrahydropyran (0.22 mol), the procedures described in Example 1 were conducted to obtain the desired product.

Yield: 51.2 g (96%).

Example 3

Preparation of (S) -3- [2- (2-Methoxyphenoxy) ethyl] -5- (hydroxymethyl) oxazolidin-2-one (Formula 2, X = oxygen)

Using 26.7 g of isobutyl 2- (2-methoxyphenoxy) ethylcarbamate 0,1, solução-dimethylformamide solution (0.1 mol), 1.60 g t-lithium butoxide (0.02 mol) and 14.3 g g of (S) -2-t-butoxymethyl oxiran (0.11 mol), the procedures described in Example 1 were conducted to obtain the desired product.

Yield: 25.6 g (96%)

Example 4

Preparation of (R) -3- [2- (2-Methoxyphenoxy) ethyl] -5- (hydroxymethyl) oxazolidin-2-one (Formula 2, X = oxygen)

Using 53.46 g of isobutyl 2- (2-methoxyphenoxy) ethylcarbamate Ν, Ν-dimethylformamide solution (0.2 mol), 3.20 g lithium t-butoxide (0.04 mol) and 28.6 g of (R) -2-t-butoxymethyl oxiran (0.22 mol), the procedures described in Example 1 were conducted to obtain the desired product.

Yield: 50.7 g (95%)

Example 5

Preparation of (S) -3- [2 [(2-methoxyphenoxy) ethyl] -5- (hydroxymethyl) oxazolidin-2-thione (Formula 2, X = sulfur)

Using 25.5 g of ethyl 2- (2-methoxyphenoxy) ethylthiocarbamate (0.1 mol) β, β-dimethylformamide solution (J. Chem. Soc., 1952, 2076; J. Chem.Soc., 1952 Tetrahedron Lett., 1969, 3631), 1.6 g of lithium t-butoxide (0.02 mol) and 17.38 g of (S) -2-oxiranylmethoxy tetrahydropyran (0.11 mol) were The procedures described in Example 1 were conducted to obtain the desired product.

Yield: 21.5 g (76%)

Example 6

Preparation of (R) -3- [2- (2-Methoxyphenoxy) ethyl] -5- (hydroxymethyl) oxazolidin-2-thione (Formula 2, X = sulfur)

Using 51.0 g of ethyl 2- (2-methoxyphenoxy) ethylthiocarbamate Ν, Ν-dimethylformamide solution (0.2 mol), lithium f-butoxide (0.04 mol) 3.2 g and 34.76 g of (R) -2-oxiranylmethoxy tetrahydropyran (0.22 mol), the procedures described in Example 1 were conducted to obtain the desired product.

Yield: 42.5 g (75%)

Example 7

(S) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxooxazolidin-5-yl} methyl methanesulfonate preparation (Formula 7, X = oxygen, Z = methanesulfonate)

53.4 g of the compound of formula 2 prepared in Example 1 (0.2 mol) and 30.86 g of triethylamine (0.3 mol) were added to dichloromethane (300mL) and the obtained solution was cooled to 0 ° C. To the solution, 25.2 g of methanesulfonyl chloride (0.22 mol) was added dropwise upon stirring. The reaction solution was stirred for three hours and water (300 ml) was added thereto. After separation of the organic layer from the mixing solution, it was dried with anhydrous magnesium sulfate and filtered. Evaporation under pressure yielded the target compound of formula 7 in a liquid phase. The obtained product was subjected without further purification to the following procedure.

Yield: 68.4 g (99%)

Example 8

(R) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxoxazolidin-5-yl} methyl methanesulfonate preparation (Formula 7, X = oxygen, Z = methanesulfonate)

Using 80.1 g of the dichloromethane solution of the compound of formula 2 prepared in Example 2 (0.3 mol), 45.5 g of triethylamine (0.45 mol) and 37.8 g of methanesulfonyl chloride (0.33 mol), The procedures described in Example 7 were conducted to obtain the desired product.

Yield: 102.5 g (99%).

Example 9

(S) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxothiooxazolidin-5-yl} methyl methanesulfonate preparation (Formula 7, X = sulfur, Z = methanesulfonate)

Using 28.33 g of the compound 2 dichloromethane solution of formula 2 prepared in Example 5 (0.1 mol), 15.18 g triethylamine (0.15 mol) and 12.6 g methanesulfonyl chloride (0.11 mol) , the procedures described in Example 7 were conducted to obtain the desired product.

Yield: 35.7 g (99%)

Example 10

(R) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxazolidin-5-yl} methyl methanesulfonate preparation (Formula 7, X = sulfur, Z = methanesulfonate)

Using 42.45 g of the compound 2 dichloromethane solution of formula 2 prepared in Example 6 (0.15 mol), 22.8 g triethylamine (0.225 mol) and 18.9 g methanesulfonyl chloride (0.165 mol) were conducted. the procedures described in Example 7 to obtain the desired product.

Yield: 53.67 g (99%).

ExampleH

Preparation of (S) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxooxazolidin-5-yl} methyl toluenesulfonate (Formula 7, X = oxygen, Z = toluenesulfonate) Using 26.7 g of solution In dichloromethane of the compound of formula 2 prepared in Example 1 (0.1 mol), 15.18 g triethylamine (0.15 mol) and 21.0 g p-toluenesulfonyl chloride (0.11 mol), the procedures described were conducted. in Example 7 to obtain the target product.

Yield: 38.7 g (92%)

Example 12

Preparation of (R) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxooxazoNdin-5-yl} methyl toluenesulfonate (Formula 7, X = oxygen, Z = toluenesulfonate)

Using 42.7 g of the dichloromethane solution of the compound of formula 2 prepared in Example 2 (0.16 mol), 24.3 g of triethylamine (0.24 mol) and 33.6 g of p-toluenesulfonyl chloride (0.176 mol) , the procedures described in Example 7 were conducted to obtain the desired product.

Yield: 62.6 g (93%)

Example 13

Preparation of (S) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxothiooxazolidin-5-yl} methyl toluenesulfonate (Formula 7, X = sulfur, Z = toluenesulfonate)

Using 28.3 g of dichloromethane solution of the compound of formula 2 prepared in Example 5 (0.1 mol), 15.18 g of triethylamine (0.15 mol) and 21.0 g of p-toluenesulfonyl chloride (0.11 mol), the procedures described in Example 7 were conducted to obtain the desired product.

Yield: 40.64 g (93%)

Example 14

Preparation of (R) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxazolidin-5-yl} methyl toluenesulfonate (Formula 7, X = sulfur, Z = toluenesulfonate)

Using 25.5 g of the dichloromethane solution of the compound of formula 2 prepared in Example 6 (0.09 mol), 13.66 g of triethylamine (0.135 mol) and 19.0 g of p-toluenesulfonyl chloride (0.1 mol) , the procedures described in Example 7 were conducted to obtain the desired product.

Yield: 35.4 g (90%).

Example 15

Preparation of (S) -5-chloromethyl-3- [2- (2-methoxyphenoxy) ethyl] oxazolidin-2-one (Formula 7, X = oxygen, Z = chloride)

Using 26.7 g of dichloromethane solution of the compound of formula 2 prepared in Example 1 (0.1 mol), 10.1 g of triethylamine (0.1 mol) and 35.7 g of thionyl chloride (0.3 mol) , the procedures described in Example 7 were conducted to obtain the desired product.

Yield: 26.3 g (92%)

Example 16Preparation of (S) -5-chloromethyl-3- [2- (2-methoxyphenoxy) ethyl] oxazolidin-2-thione (Formula 7, X = sulfur, Z = chloride)

Using 28.3 g of the dichloromethane solution of the compound of formula 2 prepared in Example 5 (0.1 mol), 10.1 g of triethylamine (0.1 mol) and 35.7 g of thionyl chloride (0.3 mol) , the procedures described in Example 7 were conducted to obtain the desired product.

Yield: 28.0 g (93%)

Example 17

Preparation of (S) -carvedylol

(S) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxooxazolidin-5-yl} methyl methanesulfonate 51.75 g (0.15 mol) prepared in Example 7 and 27.45 g ( 0.15mol) of 9H-4-hydroxy carbazole was dissolved in 450 ml of anhydrous ethyl alcohol. At solution, 31.10 g (0.225 mol) of potassium carbonate was added and refluxed for 16 hours while stirring. After complete consumption of the compound of formula 7, the reaction temperature was adjusted to room temperature. To the mixture, 150 mL of 4 N aqueous KOH was added and refluxed then six hours by stirring. The reaction mixture was cooled to room temperature and the ethyl alcohol was evaporated under reduced pressure. To the residue, water (200 mL) and dichloromethane (500 mL) were added and stirred for thirty minutes. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. Evaporation under reduced pressure generated solid waste. To the obtained residue, 260 ml of ethyl acetate was added and stirred. By filtration and washing, the (S) -carvedylolvo of formula 1 was obtained.

Yield: 44.5 g (73%)

1H NMR (300 MHz1 CDCl3): δ 1.85 (br s, 1H), 2.97 (m, 1H), 3.10 (m, 3H), 3.83 (s, 3H), 4.15 ( t, J = 7.7 Hz, 2H), 4.18-4.29 (m, 3H), 6.66 (d, J = 8.1 Hz, 1H), 6.85-6.97 (m , 4H), 7.04 (d, J = 8.1 Hz, 1H), 7.25-7.38 (m, 3H), 8.19 (br s, 1H), 8.26 (d, J = 7.8Hz, 1H).

Optical purity:> 99% ee (HPLC: Chirolsil SCA (-), effluent: acetonitrile: methyl alcohol = 2: 1 solvent mixture containing 0.1% triethylamine, effluent rate = 1 ml / min, UV detector: 254 nm, isomer retention time (S) 1 ts = 23.2 min, isomer retention time (R) 1 tR = 20.6 min).

Example 18

Preparation of (R) -carvedylol

Using 34.5 g (0.1 mol) of (R) - {3- [2- (2-methoxyphenoxy) ethyl] -2-oxooxazolidin-5-yl} methyl methanesulfonate prepared in example 8, 18.3 g (0.1mol) 9H-4-hydroxy carbazole and 20.7g (0.15 mol) potassium carbonate, the procedures described in example 17 were performed to obtain the desired (R) -carvedyl carbonate.

Yield: 28.8 g (71%).

Example 19

Preparation of (S) -carvedylol

Using 36.1 g (0.1 mol) of (S) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxazolidin-5-yl} methyl methanesulfonate prepared in Example 9, 18.3 g (0.1 mol) 9H-4-hydroxy carbazole and 20.7 g (0.15 mol) potassium carbonate, the procedures described in Example 17 were conducted to obtain the desired (S) -carvedylol.

Yield: 28 g (69%).

Example 20

Preparation of (R) -carvedylol

Using 43.3 g (0.12 mol) of (R) - {3- [2- (2-methoxyphenoxy) ethyl] -2-oxazolidin-5-yl} methyl methanesulfonate prepared in Example 10, 22.0 g (0.12mol) 9H-4-hydroxy carbazole and 24.8g (0.18 mol) potassium carbonate, the procedures described in Example 17 were performed to obtain the desired (R) -carvedyl carbonate.

Yield: 32.6 g (67%).

Example 21

Preparation of (S) -carvedylol

Using 42.1 g (0.1 mol) of (S) - {3- [2- (2-methoxyphenoxy) ethyl] -2-oxazolidin-5-yl} methyl methanesulfonate prepared in Example 11, 18.3 g (0.1 mol) 9H-4-hydroxy carbazole and 20.7 g (0.15 mol) potassium carbonate, the procedures described in Example 17 were conducted to obtain the desired (S) -carvedylol.

Yield: 26.4 g (65%).

Example 22

Preparation of (S) -carvedylol

Using 56.8 g (0.13 mol) of (S) - {3- [2- (2-Methoxyphenoxy) ethyl] -2-oxothiooxazolidin-5-yl} methyl methanesulfonate prepared in Example 13, 23.8 g (0.13mol) 9H-4-hydroxy carbazole and 26.9g (0.195 mol) potassium carbonate, the procedures described in Example 17 were performed to obtain the desired (S) -carvedyl carbonate.

Yield: 32.7 g (72%).

Example 23

Preparation of (S) -carvedylol

Using 28.6 g (0.1 mol) of (S) -5-chloromethyl- {3- [2- (2-methoxyphenoxy) ethyl] oxazolidin-2-one prepared in Example 15, 18.3 g (0, 1 mol) of 9H-4-hydroxy carbazole, 0.17 g (0.001 mol) of potassium iodide and 20.7 g (0.15 mol) of potassium carbonate, the procedures described in Example 17 were conducted to obtain (S ) -carvedylol desired.

Yield: 26.8 g (66%).

Example 24

Preparation of (S) -carvedylol

Using 42.8 g (0.15 mol) of (S) -5-chloromethyl-3- [2- (2-methoxyphenoxy) ethyl] oxazolidin-2-thione} prepared in Example 16, 27.45 g (0, 15 mol) of 9H-4-hydroxy carbazole, 0.249 g (0.0015 mol) of potassium iodide and 31.1 g (0.225 mol) of potassium carbonate, the procedures described in Example 17 were conducted to obtain (S) - desired carvedilol.

Yield: 37.8 g (62%).

Example 25

Preparation of (S) -carvedylol

26.7 g (0.1 mol) of (S) -3- [2- (2-methoxyphenoxy) ethyl] -5- (hydroxymethyl) oxazolidin-2-one were dissolved in tetrahydrofuran (100 ml) ethenylphosphine (31, 44 g, 0.12 mol) and diisopropyl azodicarboxylate (24.2 g, 0.12 mol) were successively added to the solution thereafter. The mixing solution was stirred for one hour at room temperature. A solution of tetrahydrofuran (50 mL) containing 18.3 g (0.1 mol) of 9H-4-hydroxy carbazole was added dropwise and stirred for 12 hours at room temperature. After complete consumption of the starting material, compound of formula 2, the reaction solution was evaporated under reduced pressure. Remaining residue, 300 ml ethyl alcohol and 100 ml 4N KOH aqueous solution were added and refluxed for 6 hours while stirring. The reaction mixture was cooled to room temperature and the ethyl alcohol was evaporated under reduced pressure. To the residue, water (200 mL) and dichloromethane (300 mL) were added and stirred for thirty minutes. The organic layer was separated, dried with anhydrous magnesium sulfate and filtered. Evaporation under reduced pressure generated solid waste. To the obtained residue, 150 ml of ethyl acetate was added and stirred. By filtration and washing, the target (S) -carvedylol of formula 1 was obtained.

Yield: 21.1 g (52%).

Example 26

Preparation of (R) -carvedylol

Using (S) -3- [2- (2-methoxyphenoxy) ethyl] -5-

(hydroxymethyl) oxazolidin-2-thione (32 g, 0.12 mol) prepared in Example 5, triphenylphosphine (37.7 g, 0.144 mol), diisopropyl azodicarboxylate (29.0 g, 0.144 mol) and 9H-4 hydroxycarbazole (22.0 g, 0.12 mol), the procedures described in Example 25 were conducted to obtain the desired (R) -carvedylol.

Yield: 23.4 g (48%).

The present invention provides an efficient method for preparing the target chiral carvedilol of formula 1, starting from the compound of formula 2, which is the base intermediate for the synthesis of chiral carvedilol, also by increasing the residual capacity of the hydroxyl group, alkylation with 9H-4-hydroxycarbazole and subsequent deprotection or direct coupling with 9H-4-hydroxycarbazole and subsequent deprotection.

In the above process, the base intermediate of formula 2 can easily be prepared in a highly optical pure form from commercially available departmental materials, which is one of the advantages of the present invention. This means that chiral glycidol or derivatives thereof of formula 5 and The β-protected amine compound of formula 4, which are the starting materials of the base intermediate of formula 2, are either commercially available or simply industrially produced. In addition, the preparation of the base intermediate of formula 2 from the starting materials is conducted without any reduction in optical purity, so that the key can be produced in a pure highly optical form.

Further, according to the present invention, the process does not involve any procedure that reduces optical purity during the conversion of the base intermediate of formula 2 to carvedilol. The process is conducted in a simple manner, in a smooth condition and without any extraordinary purification, so as to produce chiral carvedilol in an economical manner.

The present invention has therefore established an efficient process for preparing high optical purity chiral carvedilol using the compound of formula 2 as the base intermediate for the synthesis of chiral carvedilol, without any change in chirality and in a manner suitable for industrial bulk production.

Claims (7)

Process for the preparation of a highly optical chiral carvedilol, characterized in that it comprises a) reacting a compound of formula 2 with a halogenating agent, a sulfonating agent or a reagentemitsunobu to activate a hydroxyl group of the compound of formula 2, followed by reaction of nucleophilic substitution with 9H-4-hydroxy carbazole to produce a compound of formula 7, and b) subjecting the compound of formula 7 obtained to a protective reaction to produce the target chiral carvedilol of formula 1: <formula> formula see original document page 23 < wherein * represents a chiral center and X is oxygen or sulfur. Process according to Claim 1, characterized in that the compound of formula 2 is produced by reacting a compound of formula 4 with a chiral glycidol of formula 5, followed by the deprotection of a hydroxy protecting group: <formula> formula see where * represents a chiral center, X is oxygen or sulfur, Y is a residual group and Ri is a hydroxide protecting group. Process according to Claim 1, characterized in that the halogenating agent is selected from the group consisting of thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus tribromide and phosphorus trichloride. Process according to Claim 1, characterized in that the sulfonating agent is selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonyl chloride and nitrobenzenesulfonyl chloride. Process according to Claim 1, characterized in that the deprotection reaction of step (b) is conducted with the presence of an inorganic base. 6 Process for the preparation of a pure optical chiral carvedilol, characterized in that it comprises: - reacting the amine compound of formula 4 with a chiral glycidol compound of formula 5 by ring-opening the compound of formula 5 by the compound of formula 4 and subsequent intramolecular cyclization in situ deprotection of a hydroxy protecting group of the compound of formula 6 thus obtained to produce a compound of formula 2 reaction of the compound of formula 2 with a halogenating agent, a desulfonating agent or a reagent mitsunobu to activate a hydroxyl group of the compound of formula 2, followed by the nucleophilic substitution reaction with 9H-4-hydroxy carbazole to produce a compound of formula 7; e-subjecting the obtained compound of formula 7 to a deprotection reaction in the presence of an inorganic base to produce the target chiral carvedilol of formula 1: <formula> formula see original document page 24 </formula> 3/3 <formula> formula see original document page 25 </formula> Formula 5 <formula> formula see original document page 25 </formula> Formula 6 <formula> formula see original document page 25 </formula> Formula 7in which * represents a chiral center, X is oxygen sulfur , y is a residual group and R1 is a hydroxy protecting group.