DD301657A9 - PROCESS FOR THE PREPARATION OF INTERMEDIATE PRODUCTS FOR BIS (BENZYLPYRROLIDIN) DOPANINE AGONISTS - Google Patents

Abstract

A process for the preparation of benzylpyrrolidine derivatives of the formula (II) in which R ind 2 is hydrogen or lower alkyl or pharmaceutically acceptable salts thereof which comprises protecting the amine function of proline, the resulting compound into a derivative is described which converts to a ketone with an organometallic compound, converts that derivative with a suitable organometallic compound to a ketone, reduces the ketone function to a methylene group, and cleaves the protecting group on the amine function; and optionally converting the resulting compound to the free base or a pharmaceutically acceptable salt thereof. The compounds of formula (II) are important intermediates for the preparation of bis (benzylpyrrolidine) dopamine agonists. Formula (II)

Description

Field of application of the invention The invention is used in the field of intermediates for pharmaceuticals, in particular of dopamine Agonists for the treatment of hypertension, congestive heart failure and acute renal failure in mammals. Drugs with the pharmacological action of dopamine are referred to as dopamine agonists and dopamine is one

on the market sympathomimetic agent with significant dopaminergic effect in the periphery. Some lymphatic hormetic agents appear to exert an effect on dopamine receptors in the central nervous system. In the

Peripheral dopamine receptors occur especially in the vascular beds of the viscera and kidneys, where they as Mediators of vasodilation. Dilatation in these beds is important in the treatment of shock and acute Heart failure, as these beds are often narrowed in critical conditions. Dopamine is used in the treatment of these disorders. It can also be used to induce diuresis,

probably at least partially as a result of renal vasodilation.

Dopamine hydrochloride (or SA-dihydroxyphenethylamine hydrochloride) has the following formula:

HO

H ₂ CH ₂ NH ₂ .HCl

Dopamine (3-hydroxytyramine) can be prepared from tyramine by sequential nitration to 3-nitrotyramine, reduction to 3-aminotyramine by catalytic hydrogenation, and diazotization to 3-hydroxytyramine.

Dopamine hydrochloride is a white crystalline powder which decomposes at about 241 ^° C, is readily soluble in water, is soluble in alcohol and is virtually insoluble in chloroform and ether.

Dopamine is a natural catecholamine formed by decarboxylation of 3,4-dihydroxyphenylalanine (DOPA). It is a precursor of norepinephrine in noradrenergic nerves and also acts as a neurotransmitter at certain sites of the central nervous system, especially in the nigrostriatal tract, and in a few peripheral sympathetic nerves.

In the central nervous system and the vascular beds of mesentery, coronary arteries and kidneys, it responds to dopamine receptors that are distinct from α and β adrenoreceptors. Haloperidol is an antagonist for the latter dopamine receptors. In the above vascular beds, it causes vasodilation. Renal vasodilation may be a stimulant for diuresis. Dopamine also has a moderate activity as a β-agonist and a weak activity as an α-agonist, with some of these effects being due to norepinephrine released by dopamine. During intravenous infusion with a low infusion rate, usually only vasodilation in the vascular beds of the mesentery, coronary arteries and kidneys is predominant and sometimes negative pressure occurs. An infusion of medium infusion rate will increase the heartbeat and contraction force, as well as cardiac output, and increase blood pressure accordingly. At high infusion rates, in some recipients, a-adrenergic vasoconstriction in the vascular beds of mesentery, coronary arteries and kidneys may dominate over dopaminergic vasodilation. Dopamine is used in the treatment of shock conditions, where it has several advantages. First, vasodilation can often be effected in two organs most likely to be ischemic in shock (kidneys and small intestine); Blood can be transported by the skeletal muscles to the more vital organs, the stimulation of the heart improves the usually disturbed heart function, and the diuresis is for the heart

Preservation of kidney function helpful. Although dopamine is currently the drug of choice in conditions of shock, in a not inconsiderable number of cases no response is observed. Dopamine is also used to treat acute heart failure. Decreased vascular resistance reduces post-cardiac stress, cardiostimulating action improves cardiac output, and diuresis reduces the number of edema.

Characteristic of the known state of the art

U.S. Patent 4,613,606 discloses a number of tetrahydroisoquinoline derivatives which are stated to be catabolic channel blockers and are useful as such for the treatment of cardiovascular disorders, including angina, hypertension and congestive heart failure.

European Patent Application No. 294973 describes a number of dopamine β-hydroxylase inhibitors (DBH inhibitors). Dopamine is hydroxylated by DBH to norepinephrine in the presence of oxygen and ascorbic acid. This European application discusses numerous known DBH inhibitors which are believed to be effective in the treatment of hypertension. Methods for the synthesis of these compounds are also described.

Object of the invention

The aim of the invention is to provide certain intermediates for new drugs for the treatment of hypertension, congestive heart failure and / or acute renal failure.

Explanation of the essence of the invention

The invention has for its object to provide certain intermediates for new drugs for the treatment of hypertension, congestive heart failure and / or acute kidney failure. These new drugs have the general formula (I):

(I)

wherein the groups R _{1 are} independently hydrogen, lower alkyl, -C (O) R ₃ ) and -C (O) NR ₃ R ₄ , wherein R ₃ and R _{4 are} independently lower alkyl, optionally substituted phenyl or phenyl-lower alkyl; R _{2 is} hydrogen or lower alkyl; X represents (CH ₂ U- or - (CH ₂ ) "Y (CH ₂ )" -, wherein m is an integer of 1 to 10, η represents an integer of 1 to 3 and Y represents oxygen or sulfur.

The invention thus relates to a process for the preparation of intermediates for the preparation of the compounds of formula (I), i. of compounds of general formula (II):

(II)

in which R _{2 is} hydrogen or lower alkyl; or pharmaceutically acceptable salts thereof, characterized in that one provides the amine function of proline with a protecting group, the resulting compound is converted into a derivative which can be converted with an organometallic compound in a ketone, this derivative with a suitable organometallic compound to a ketone converts the ketone function into a methylene group and cleaves the protective group on the amine function; and optionally converting the resulting compound to the free base or a pharmaceutically acceptable salt thereof.

In the following description, reference will be made to the present general structural formulas indicated by Roman numerals, numerals or letters, in which like symbols represent the same molecular units throughout.

definitions

"Lower alkyl" means a branched or unbranched saturated hydrocarbon chain having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, i-propyl, tert-butyl, butyl, i-butyl and the like, unless otherwise specified. "Optionally "means that the subsequently described event or circumstance may or may not occur and that the description covers both the cases in which this event or circumstance occurs and the cases in which this does not occur Case is.

"Protecting group" means any suitable chemical group commonly used in organic chemistry to modify one or more of the more important functional groups in a molecule to selectively effect a chemical reaction at another reactive site in a multifunctional molecule typically formed in a selective manner and is stable to subsequent reactions on the molecule and selectively removed from reagents that do not attack the regenerated functional group Suitable protecting groups for the amino group are carbamates such as methyl carbamates and derivatives thereof such as cyclopropylmethyl, diisopropylmethyl , 9-fluorenylmethylcarbamates and the like, substituted ethylcarbamates such as 2,2,2-trichloroethyl, 2-haloethyl and the like, substituted propyl and isopropyl carbamates such as 1,1-dimethylpropyl, 1-methyl 1 -phenylethyl and derivatives, isobutyl, t-butylcarbamate-amylcarbamate, vinyl and allyl carbamate, phenyl and substituted phenylcarbamate, benzylcarbamate, and derivatives, e.g. p-methoxybenzyl, 3,5-dimethoxybenzyl, o- and p-nitrobenzyl, halobenzyl and the like; Amides and their derivatives, e.g. N-acetyl and derivatives such as N-dichloroacetyl, N-trifluoroacetyl and the like, substituted N-propionyl derivatives such as N-3-phenylpropionyl and derivatives, no-nitrocinnamoyl and the like, cyclic imide derivatives such as N-phthaloyl, N-2,3 -Diphenylmaleoyl, and the like.

The term "pharmaceutically acceptable salts" refers to salts of the present compounds which are neither biologically nor otherwise undesirable These salts are treated with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid or organic acids Acids such as acetic, propionic, glycolic, pyruvic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, ethanesulfonic, p-toluenesulfonic and the like.

The compounds prepared according to the invention have an asymmetric center and can therefore be prepared as individual stereoisomers or as mixtures of stereoisomers. The individual stereoisomers can be obtained by using an optically active starting material, by cleaving a racemic or non-racemic mixture of an intermediate at any suitable stage of the synthesis, or by cleaving the compound of formula (II). Both the individual stereoisomers and mixtures (racemic and non-racemic) of these stereoisomers are to be detected by the present invention.

The system used to denote the present intermediates will now be illustrated by the example of compounds of formula (I).

A racemic compound of formula (I) in which R ₁ and R _{2 are} hydrogen and X is - (CH ₂ ) _m -, where m is 7, is designated as: (± M, 7-bis- (2 - (3,4-dihydroxybenzyl) pyrrolidyllheptan.

A racemic compound of formula (I) in which Ri and R _{2 are} hydrogen and X is - (CHj) _n Y (CH ₂ I _n -, where η is 2 and Y is sulfur, is designated as: ( ±) -2,2-Bis- [2- (3,4-dihydroxybenzyl) pyrrolidyldiethylthioether.] A racemic compound of the formula (I) wherein R _{1 is} -C (O) CH ₃ , R _{2 is} 5-methyl and X represents - (CH ₂ ) _m -, where m is 4, is designated as: (±) -1,4-bis [2- (3,4-diacetoxy-5-methylphenylmethyl) pyrrolidyl] butane.

Preferred embodiments

Before describing the subject intermediates and methods of preparing them, it is to be understood that the present invention is not limited to the specifically described intermediates and methods which, of course, may be varied. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not to be construed restrictively, as the scope of the present invention is defined only by the claims.

It should also be noted that in the present specification and claims, the singular forms "a,""the,""the" and "the" are also intended to include the plural, unless the context clearly dictates otherwise. In the following examples, unless otherwise specified, parts by weight, the temperature is room temperature (20 to 30 ⁰ C) and the pressure is close to or equal to the atmospheric pressure.

production method

Reaction scheme I

A process for preparing the optically active isomers of the compounds of formula (II) is shown in Reaction Scheme I.

Reaction scheme I

LEVEL Ca)

LEVEL Cb)

T)

C2 ·)

O Il CPhO) ₂ Pv

HN

LEVEL Cc)

C3 ·)

CS *)

CH ₃ O

CH ₃ O

(β ¹ )

LEVEL Cd)

CK ₃ O

CH ₃ O

'Э

, CH ₃ O

HN LEVEL Ce) ^CH 3 °

C8 ·)

General Description of the Steps of Reaction Scheme I

The preferred method of preparing the compounds of formula (II) in the form of their optical isomers, wherein R _{2 is} hydrogen, starts from commercially available optically pure R or S-proline.

Stage (a)

Step (a) involves the protection of the amine function of R- or S-proline, preferably in the form of the trifluoroacetyl derivative. Typically, the amine of formula (1 ') is dissolved in an inert solvent such as e.g. Benzene, toluene, acetonitrile, diethyl ether, chloroform, methylene chloride or, preferably, tetrahydrofuran, having from 1 to 5 molar equivalents, preferably about 2 molar equivalents, of a trifluoracetylating agent, preferably ethyltrifluoroacetate, in the presence of about 1.0 to about 2 equiv, preferably about 1 , 5molaren equivalents, of a tertiary organic base, such as

Pyridine, N-methylpiperidine, 4-dimethylaminopiperidine and the like, preferably 1,1,3,3-tetramethylguanidine. The reaction is carried out at a temperature of about 0 to 40 ⁰ C, preferably about 25 ° C, about 10 minutes to 4 hours, preferably about 30 minutes. When the reaction is virtually complete, the product of formula (2 '), 1-trifluoroacetyl-R- or S-proline, is isolated by conventional methods.

Stage (b)

In step (b), the carboxyl group of the protected amine of formula (2 ') is converted to a derivative which upon reaction with an organometallic compound provides a ketone. Methods of converting carboxyl groups to ketones are well known and include conversion of the carboxyl group to an acid halide followed by reaction thereof with a lithium dialkyl copper reagent or organocadmium reagent, or conversion of the carboxyl group to a tertiary amide and reaction thereof with a Grignard reagent or an organotithium derivative. Such reactions are described in more detail in March, "Advanced Organic Chemistry", pp. 439-440 (2nd edition) The preferred method is to convert the carboxyl group with diphenyl phosphoric acid to a mixed anhydride, most preferably one R- or S-2-carboxy-i-trifluoroacetylpyrrolidine anhydride with diphenylphosphoric acid Typically, the protected amine of formula (2 ') is dissolved in an inert solvent as defined above, preferably methylene chloride, and treated with 0.5 to 1, 5 molar equivalents, preferably about 1 molar equivalent, of an organochlorophosphate, preferably diphenylchlorophosphate, in the presence of about 1.0 to about 40 equivalents, preferably about 1.5 molar equivalents, of a tertiary organic base such as pyridine, N-methylpiperidine and The reaction is carried out at a temperature of about -20 ° C to 20 ° C, preferably N-methylmorpholine ⁰ C, preferably about 0 ⁰ C for about 5 minutes to 1 hour, preferably for about 10 minutes, followed by a temperature of 0 ° C to 30 ⁰ C, preferably about 25 ⁰ C, for about 5 minutes to 1 hour, preferably about 10 minutes, felt through. When the reaction is virtually complete, the product of formula (3 ') is isolated by conventional procedures. The R- or S-2-carboxy-i-trifluoroacetylpyrrolidine anhydride with diphenylphosphoric acid of the formula (3 ') is hygroscopic and unstable to heat and moisture and is therefore preferably used without delay in the next step.

Stage (c)

In step (c), the R- or S-2-carboxy-i-trifluoroacetylpyrrolidine anhydride is converted with diphenylphosphoric acid of the formula (3 ') into a ketone of the formula (6'). Typically, the compound of formula (3 ') as defined above in an inert solvent, preferably tetrahydrofuran, and cooled to a temperature of about -100 ⁰ C to -50 ° C, preferably about -6O ⁰ C to -70 ⁰ C, cooled. To this cold solution is added 1 to 2 molar equivalents, preferably about 1.1 molar equivalents, of a Grignard reagent of formula (5 ') prepared from commercially available 4-bromo veratrole at such a rate that the temperature is in the preferred range Area is held. The reaction mixture is then allowed to come to a temperature of about ⁰ ° C to 30 ^° C, preferably about 25 ^° C, within about 5 to 30 hours, preferably about 14 hours. When the reaction is virtually complete, the product of formula (6 '), R- or S-2- (3,4-dimethoxybenzoyl) -1-trifluoroacetylpyrrolidine, is isolated and purified by conventional methods, preferably chromatography.

Stage (d)

In step (d), the ketone of formula (6 ') is reduced to a compound of formula (7'), ie R- or S-2- (3,4-dimethoxybenzyl) -1-trifluoroacetylpyrrolidine. Typically, the compound of formula (6 ') is dissolved in a solvent as defined above, preferably methylene chloride. To this solution is added 5 to 20 molar equivalents, preferably about 11 molar equivalents, of a reducing agent, preferably triethylsilane / boron trifluoride-etherate mixture. The reaction is conducted at a temperature of about 0 ° C to 30 ° C, preferably about 25 ⁰ C, about 1 to 7 days, preferably carried out for approximately 3 days. When the reaction is virtually complete, the product of formula (7 ') is isolated by conventional procedures.

Stage (s)

In step (e), the amine protecting group is removed from the compound of formula (7 '). Typically, the compound of formula (7 ') is dissolved in a protic solvent, e.g. Ethanol, n-propanol, n-butanol, t-butanol and the like, preferably isopropanol, and to this solution are added 5 to 50 molar equivalents, preferably about 20 molar equivalents, of an acid, e.g. Sulfuric acid, HBr and the like, or preferably 12.5 molar hydrochloric acid. The reaction is carried out at the reflux temperature of the chosen solvent, preferably about 70 to 90 ° C, for about 8 to 48 hours, preferably about 24 hours. When the reaction is virtually complete, the product of formula (8 '), R- or S-2- (3,4-dimethoxybenzyl) pyrrolidine, is isolated by conventional methods.

It should be noted that optically pure compounds according to the invention can also be obtained by applying a reaction scheme leading to a racemic mixture and then carrying out a resolution of the optically pure compounds from the mixture by conventional methods. However, the preferred method of producing optically pure compounds is that shown in Reaction Scheme I.

Experimental details of the reaction steps

Additional information on the steps of Reaction Scheme I will be given below. Unless indicated otherwise, parts are parts by weight, the temperature is room temperature (20 ⁰ C to 30 ⁰ C) and the pressure is close to or equal to the atmospheric pressure.

Reaction scheme I

Detailed description of steps (a) to (e)

Step (a)

To a 500 ml round bottom flask was added 20 g (0.174 mol) of compound (V), ie R-proline. To this was added 100 ml of dry THF and SOg (0.34 mol) of ethyl trifluoroacetate. Solution / flask was purged with argon and 30 g (0.261 mol) of 1,1,3,3-tetramethylguanidine was added dropwise. The solution was stirred until all of the R-proline (V) had dissolved (approximately 35 minutes). The solvent was removed in vacuo and the residue was dissolved in CH ₂ Cl ₂ (200 ml). The solution was washed with 6N HCl (aqueous, 2 x 100 ml) and the organic layer was separated, dried with sodium sulfate and filtered. The solvent was removed in vacuo to afford an oil which crystallized on standing to 1-trifluoroacetyl-R-proline. Yield: 29g, 79%; Mp. 48 ° C-51 ⁰ C.

Stage (b)

29g 1-trifluoroacetyl-R-proline (0.137 mol) were dissolved in a 1-liter round bottom flask in CH ₂ CI ₂ (300ml) and cooled to 0 ⁰ C. To this solution was added 36.9 g (0.137 mol) of diphenyl chlorophosphate, followed by 15.27 g (0.151 mol) of 4-methylmorpholine. After stirring for 10 minutes at 0 ° C, the reaction mixture was allowed to come to room temperature and passed for an additional 10 minutes. The solution was then diluted with 600 ml of dry diethyl ether. After filtration, the filtrate was washed with a saturated NaHCO ₃ aqueous solution, and then the organic layer was separated, dried with magnesium sulfate and filtered. The solvent was removed in vacuo to afford a solid, ie R-2-carboxy-trifluoroacetylpyrrolidine anhydride with diphenylphosphoric acid, which was hygroscopic and unstable to heat and moisture (90%, 54.8 g).

Stage (c)

Into a 250 ml round bottom flask was added 4.51 g (0.186 mol) of magnesium turnings and 100 ml of dry THF. Iodine (a crystal) was added, followed by the dropwise addition of 27 g (0.124 mol) of 4-bromo veratrole. The reaction mixture was heated to reflux after the addition of the first drops of 4-bromo veratrole until the color of the iodine disappeared. Then the remainder of 4-bromo veratrole was added dropwise. The mixture was held for 2 hours at reflux, then the solution was cooled to room temperature, and a solution of 54g was 0.123 mol) was added R-2-carboxy-itrifluoracetylpyrrolidinanhydrid with diphenylphosphoric acid in 250 ml dry THF at -70 ⁰ C. The rate of addition was adjusted so that the reaction temperature below -60 ⁰ C remained. Once the addition was complete, the mixture was warmed to room temperature and stirred for 14 hours. Then it was poured into a saturated ammonium chloride solution (500 ml) and shaken. The organic layer was separated and dried with magnesium sulfate and filtered. The solvent was removed in vacuo to provide an oil. This oil was flash chromatographed in hexane-ethyl acetate (1 -.1) to yield 20.4 g (50%) of the compound of formula (6 '), ie, R-2- (3,4-dimethoxybenzoyl) -1-trifluoroacetylpyrrolidine, m.p. . 121 ⁰ C-123 ^e C [a] g ^s = 65 ⁰ C (c = 1.2 in CHCl _3).

Stage (d)

4.9 g (0.015 mol) of R-2- (3,4-dimethoxybenzoyl) -1-trifluoroacetylpyrrolidine were dissolved in a 500 mL round bottom flask in 50 mL of dry CH ₁ Cl ₂ . To the solution were added 20 g (0.172 mol) of triethylsilane and 50 ml of BF _3. Et ₂ O. The reaction mixture was stirred at room temperature for 3 days, after which a saturated potassium carbonate solution was carefully added dropwise. As soon as no further gas evolved as a result of the addition of K ₂ CO ₃ , 100 ml of CH ₂ Cl _{2 were} added. The mixture was shaken, the three-phase mixture was filtered through a filter with glass frits, and the organic layer was separated and dried with magnesium sulfate. Removal of the solvent in vacuo afforded R-2- (3,4-dimethoxybenzyl-i-trifluoroacetylpyrrolidine in the form of an oil (3.2g, 68%) which could be used without further purification.

Stage (s)

To a solution of 3.2 g (0.010 mol) of R-2- (3,4-dimethoxybenzyl) -1-trifluoroacetylpyrrolidine in 50 ml of isopropyl alcohol was added 15 ml of 12.5 M HCL. The mixture was then refluxed until all of the starting material had disappeared (approximately 24 hours). The solvent was removed in vacuo to afford an oil that could be crystallized from isopropyl alcohol / ether to give needles of R-2- (3,4-dimethoxybenzyl) pyrrolidine (2.5 g, 97%; 165 ⁰ C-167 ⁰ C).

Claims (1)

Process for the preparation of a compound of general formula (II) (II) CH ₃ O in which R _{2 is} hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof, characterized by capping the amine function of proline, converting the resulting compound into a derivative which can be converted to a ketone with an organometallic compound, forming this derivative with a suitable organometallic compound Converts ketone, reduces the ketone function to a methylene group and cleaves the protective group on the amine function; and optionally converting the resulting compound to the free base or a pharmaceutically acceptable salt thereof.