DD213924A5 - PROCESS FOR THE PRODUCTION OF SORBINIL - Google Patents

Abstract

Sorbinil is obtained by optical resolution of racemic 2,3-dihydro-spiro-6-fluoro & 4H-1-benzopyran-4,4'-imidazolidine) -2 ', 5-dione either (a) by direct separation over the (-) - 3-aminomethyl-pinane salt of sorbinil or (b) by a double-separation technique over a mother liquor concentrate of either the (+) - 3-aminomethylpinane or the (-) - 2-amino-2-norpinane salt of sorbinil, then through the quinine salt of sorbinil Sorbinil is also obtained by cyclizing S-6-fluoro-4-ureiodochroman-4-carboxylic acid, which in turn is prepared by separating racemic 6-fluoro-4-ureidochroman-4-carboxylic acid over diastereomeric salts with entw.D- (+ ) - (1-phenethyl) amine or L - (-) - ephedrine. 6-fluoro-4-chromanone, a sorbinil intermediate, is regenerated from enantiomeric and mixtures of enantiomeric and racemic compounds, as major by-products in the synthesis of sorbinol. The regenerated intermediate is useful in the synthesis of additional sorbinil.

Description

/ -

Process for the preparation of sorbinil Field of application of the invention

S-6-fluorospiro [chroman-4, 4'-imidazolidine] -2 ', 5'-dione, also as S-2,3-dihydro-6-fluoro-spiro [4H-1-benzopyran-4, 4'-imidazolidine] 2 ', 5'-dione (US designation sorbinil), the following formula (5) is an extremely potent aldose reductase inhibitor of particular value in the effective control of chronic complications of diabetes mellitus (Sarges, US Pat. PS 4 130 714). The present invention relates to an improved process for the preparation of sorbinol and intermediates used in this improved process.

Characteristic of the known technical solutions

Heretofore, sorbinil has been prepared by separating the corresponding racemic 6-fluoro spiro [chroman-4, 4'-imidazolidine] -2 ', 5'-dione of the following formula (3) using highly toxic brucine as a means of cleavage or separation in large volumes of solvent prepared (US-PS 4,130,714).

Aim and presentation of the essence of the invention

Surprisingly, it has now been found that the cleavage or separation of the racemate either (a) directly via the (-) - 3-Aminomethylpinansalz of sorbinol or (b) by a Doppeltrennmitteltechnik a mother liquor concentrate of either the (+) - 3-Aminomethylpinan- or the (-) - 2-amino-2-norpinan salt,

thereafter via the quinine salt. Good yields of sorbinil are obtained with much lower volumes of solvent, while avoiding the use of a highly toxic release agent. The performance of this process is further improved by isolating the undesired enantiomer from mother liquors and returning to fresh racemate via the precursor 6-fluoro-4-chromanone.

Surprisingly, we have also found that the separation of the precursor of 6-fluoro-4-ureidochroman-4-carboxylic acid of the following formula (4) as either D - (+) - (1-phenethyl) amine or L - (-) ephedrine salt followed by simple cyclization in glacial acetic acid provides an improved method for sorbinil. The racemic precursor is conveniently derived from the above racemic imidazolidine of formula (3) via the amino acid of the following formula (2). In this way, excellent yields of sorbinil are obtained with much lower solvent volumes and with readily available, relatively cheap optically active amines. At the same time, the use of a highly toxic cleavage or release agent is avoided. The performance of this process is further improved by isolating the undesired enantiomer from mother liquors and returning to fresh racemate via the precursor 6-fluoro-4-chromanone.

The synthesis of sorbinil by optical resolution of RS-2,3-dihydro-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2 ', 5'-dione (the racemic, sorbinil-corresponding compound) or the precursor 6-Fluoro-4-ureidochroman-4-carboxylic acid provides at least equal yields of the undesired enantiomer of sorbinil or its precursor (both contaminated with the corresponding racemate). The overall performance of the process is greatly enhanced by conversion of these by-products to the sorbinil intermediate 6-fluoro-4-chromanone, which is then reconverted to sorbinil. Not only is the overall yield of sorbinil greatly increased, but those with these byproducts (the

necessarily in Sorbinil or its precursor at least equal yields are formed) associated disposal problems are avoided.

The present invention is applicable not only to the original synthesis of sorbinil with optical resolution of the racemate with brucine (Sarges, U.S. Patent 4,130,714), but also to the current, more recently discovered methods.

Sorbinil has also recently been prepared by an alternative synthesis which induces the required chirality during the synthesis sequence. (Sarges, U.S. Patent 4,286,098).

The present invention comprises a process for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof which comprises the steps of

(a) crystallizing the (-) - 3-aminomethylpinane salt of sorbinol from a solution of racemic hydantoin of the following formula (3) and

(b) converting the aminopinan salt into sorbinil or its pharmaceutically acceptable salt

includes.

The present invention also includes a process for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof which comprises the steps of

(a) crystallizing either the (+) - 3-aminomethylpinnane or the (-) - 2-amino-2-norpinane salt of the enantiomer of sorbinol from a solution of racemic hydantoin of the following formula (3),

(b) isolating a concentrate of sorbinil from its mother liquor,

(c) crystallizing the quinine salt of sorbinil from a solution of sorbinol concentrate and

(d) comprising converting the quinine salt of sorbinil to sorbinil or a pharmaceutically acceptable salt thereof.

The invention further encompasses sorbinil chiral amine salts as intermediates wherein the chiral amine is selected from (-) - 3-aminomethylpinane, (+) - 3-aminomethylpinane / (-) - 2-amino-2-norpinan and quinine. Particularly valuable are those amine salts which are isolated in crystalline form, namely the (-) - 3-aminomethyl-pinane salt and the quinine salt of sorbinol

3-Aminomethyl-pinane or 2-amino-2-norpinane have the following formulas NH '

and

Further, the invention includes a process for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof which comprises the steps of

(a) separating a crystalline S-6-fluoro-4-ureidochromane-4-carboxylic acid of the following formula (6) with D- (+) - (1-phenethyl) amine or L - (-) - ephedrine of the formulas

CH CH CH OH

1-3 I 3 I 3 l

H _n N-CHC, H _c HN or CH-CHC-H. ₁

zoo 'bo

from a racemic compound of the later formula (4) and

(b) cyclizing the phenethylamine · or ephedrine salt in excess glacial acetic acid to form the sorbini. ,

Also within the scope of the present invention are the intermediate salts of S-6-fluoro-4-ureidochromane-4-carboxylic acid with either D- (+) - (1-phenethyl) amine or L- (-) - ephedrine,

The reaction scheme contains the above synthetic routes to sorbinil and the back-conversion of by-products into 6-fluoro-4-chromanone according to the invention.

Thus, the present invention further comprises a process for regenerating purified 6-fluoro-4-chromanone (1) from neutron.

benprodukt-R- or a mixture of R- and RS-6-fluoro-spirofchroman-4,4'-imidazolidine -2 ', 5'-dione [(7) or (7) and (3)], or a mixture R- and RS-6-fluoro-4-ureidochroman-4-carboxylic acid [(8) or (8) and (4)], or a cationic salt thereof, comprising the steps of:

(a) hydrolysis in the presence of an aqueous-inorganic base to form an intermediate amino acid which is .R- or a mixture of R- and RS-4-amino-6-fluoro-chroman-4-carboxylic acid (2),

(b) decomposing the intermediate amino acid in an aqueous solvent with a chlorinating agent to form a mixture of 6-fluoro-4-chromanone and 6-fluoro-4-chloroiminochroman [mixture (9)], and

(c) hydrogenating the mixture of 6-fluoro-4-chromanone and 6-fluoro-2-chloroiminochroman over a noble metal catalyst in an aqueous or aqueous-organic solvent to give the purified 6-fluoro-4-chromanone (1), suitable for recycling additional sorbinol.

scheme

HOOC NH.

N-C =O HOOC NH

The term "cationic salt" includes, but is not limited to, alkali metal salts (e.g., sodium, potassium), alkaline earth salts (e.g., calcium, magnesium), and salts with amines (e.g., ammonia). In a preferred embodiment, the salt is one with an optically active amine used in the resolution of racemate (3) or (4). If the regeneration of 6-fluoro-4-chroraanon

(7) or a mixture of (7) and (3), the most preferred salts are those with. Brucine (used by Sarges, supra) or (-) - 3-aminomethyl-pinane, (+) - 3-aminomethyl-pinane, (-) - 2- amino-2-norpinan or quinine (all used by Sysko, above). Of the latter, most preferred is (-) - 3-aminomethyl-pinane, since in this case only one optically active amine is used, which facilitates the recovery of the amine. Is the regeneration of 6-fluoro-4-chromanone from (8) or a mixture of

(8) and (4) are the most preferred salts with D - (+) -

(1-phenethyl) amine or L - (-) - ephedrine (used by Cue et al., Supra).

When the salt is that of an optically active amine, another preferred embodiment of the invention is to recover the optically active amine in step (a) above by extracting the basic aqueous reaction mixture with a water immiscible, reaction inert organic solvent. The amine is recovered from the extract by standard methods of evaporation, precipitation and / or distillation. The term "reaction-inert solvent" as used herein refers to a solvent which does not interact with starting materials, reagents, intermediates or product such that the yield or purity of the desired product is not substantially reduced, in the present case the optically active amine and ultimately, the 6-fluoro-4-chromanone, both of which are to be recycled to give additional sorbinol.

The term "chlorinating agent" refers to any chlorinating agent commonly used in the art, including

but not limited to chlorine, N-chloro-lower alkanoic acid amides (eg N-chloroacetamide), hydrocarbyl dicarboximides (eg N-chlorosuccinimide, phthalimide and the like), N-lower alkanoylanilides, 3-chloro and 3 , 5-dichloro-5,5-dimethylhydantoin chloride hydrohalides (eg, pyridinium perchloride hydrochloride), and lower alkyl hypochlorites (eg, tertiary butyl hypochlorite). Preferred reagents are N-chlorosuccinimide or sodium hypochlorite (equivalent to Cl "+ NaOH). When N-chlorosuccinimide is used as the chlorinating agent, the pH of step (a) is preferably adjusted to 4 to 5.5 and maintained during the decomposition step (b). When sodium hypochlorite is used as the chlorinating agent, it is preferable that the pH is not lowered from the step (a), which avoids the release of chlorine gas from the system at the decomposition step (b).

The methods of the invention are easy to carry out. For the preparation of sorbinil by direct cleavage or separation, the racemate is slurried or dissolved in a solvent, suitably a lower alkanol or a mixture of lower alkanols, with heating from 5 ° to 90 ° C. The. preferred solvent is a mixture of methanol and isopropanol in a volume ratio of about 1: 1, conveniently heated to reflux (about 69 to 71 ⁰ C). Substantially one molar equivalent of (-) - 3-aminomethyl-pinane, conveniently dissolved in one part of the solvent, is added to the hot slurry or solution to form a solution of diastereomeric salts. The amine salt solution is slowly cooled to about 0 to 5 ^° C. and the resulting crystalline solids are granulated, usually for a period of time before isolation. Such slow cooling and granulation minimizes entrapment of the undesired diastereomeric salt. The volume of solvent is chosen to maximize the recovery of sorbitan salt while minimizing the amount of undesired enantiomeric salt that crystallizes. Does the product contain a significant amount

Amount of the latter, it is easily removed by optical recrystallization from the same alkanol or a mixed alkanol solvent. The (-) - 3-aminomethylpinan salt of sorbinil is then converted to SorbLnil or a pharmaceutically acceptable salt thereof according to standard methods well known in the art. For example, the amine salt is distributed between at least one equivalent of aqueous acid and a water-immiscible organic solvent, and sorbinol. obtained by separating and concentrating the organic layer and / or adding a non-solvent. When a pharmaceutically acceptable cationic salt is desired, the sorbinil is back-extracted into water containing essentially one equivalent of the cation in base form (e.g., NaOH, KOH, NH ₄ OH) and the salt from the aqueous layer by concentration or Freeze-drying isolated.

For the preparation of sorbinil by the so-called double-separation technique, the first step of the process is completely analogous to the direct process, except that the enantiomer of sorbinol is used directly as either (+) - 3-aminomethylphenyl or (-) - 2-amino- 2-norpinane salt, yielding a mother liquor concentrate of either the (+) - 3-aminomethyl-pinane or the (-) - 2-amino-2-norpinane salt of sorbinil. Each of these concentrates is then made into a partially separated concentrate of sorbinil by standard methods (as detailed above). transformed. Now enough separation is achieved to complete by crystallizing sorbinil as the quinine salt. The conditions used are essentially as set forth above, but quinine now replaces the aminopinane derivative, with about 4: 1 isopropanol: methanol now being the preferred alkanol solvent. The quinine salt is also optically recrystallized, as detailed above, and finally converted to sorbinil according to the standard procedures set forth in detail above.

The racemic 6-fluoro-spiro [4H-1-benzopyran-4,4'-imidazoline] -2 ', 5'- required for the present sorbinil processes

dion is derived from 6-fluoro-4-chromanone according to the method of Sarges, US Pat. No. 4,130,714. The efficiency of the overall process is greatly increased by obtaining the enantiomer of sorbinil (usually also containing racemate) from mother liquors. The latter is recycled via 6-fluoro-4-chromanone to give additional racemate suitable for optical resolution to sorbinil. The 6-fluoro-4-chromanone for recycle is regenerated by the methods described below.

The alternative method according to the invention is also easy to carry out. Racemic 6-fluoro-4-ureidochroman-4-carboxylic acid (obtainable from 6-fluoro-4-chromanone according to the method of Sarges, US Pat. No. 4,130,714) is treated with D - (+) - (1-phenethyl) amine or L - (-) - ephedrine combined in a suitable solvent. Usually, acid and amine are used at about mole per mole, although the amount of amine can be varied from as low as 0.5 mole / mole to a large excess. To prevent precipitation of racemic free acid, it is preferred to use at least about 1 mole / mole.

The solvent is usually of an organic nature. Methanol is especially good with any amine. Acetone is also a preferred solvent when the amine is ephedrine. An-.dere solvents which are suitable for the process according to the invention are easily determined by simple experiments. The salts generally form at elevated temperatures, e.g. B. 40 to 100 ⁰ C, conveniently between 40 ⁰ C and reflux temperature of the solvent. It is not essential that complete dissolution occur at each stage, ie, the salt can crystallize before the racemic starting acid (4) has completely dissolved. The crystallized, separated salt is recovered after lowering the temperature, for example to 0 to 4 0 ⁰ C, and, if desired, digesting the product by stirring for 1 to 24 hours at the temperature used for isolation. If further purification of the separated salt is desired, the salt initially recovered may be re-slurried or

be recrystallized from the same or a different solvent, as stated above.

The separated salt is converted, if desired, to the acid form by standard techniques of acidification and extraction. The separating agent is, if desired, recovered from the aqueous raffinate by standard techniques of basification and extraction.

The separated free acid or conveniently the Aminsalζ itself becomes easily in sorbinil. converted by heating to 7 0 to 110 ⁰ C in glacial acetic acid. This step conveniently takes place on a steam bath at 90 to 100 ^° C.

The required racemic ureidocarboxylic acid (4) is prepared by total synthesis, e.g. B ... by conversion of 6-fluoro-4-chromanone to amino acid (2) by Strecker's synthesis, followed by N-aminocarbonylation. It is preferable to prepare the intermediate amino acid (2) from the racemic hydantoin (3) which, in turn, is readily prepared from 6-fluoro-4-chromanone in a single step by the method of Sarges, U.S. Patent 4,130,714 ,

The conversion of the hydantoin (4) into the amino acid (2) takes place under various aqueous, basic conditions. Suitable bases are sodium, potassium and barium hydroxide, in excess (eg., 2 to 4 moles of base / mole of hydantoin), used in water at 75 to 100 ⁰ C, conveniently at reflux. The preferred base is sodium hydroxide, of which about 4 moles of base / mole of hydantoin are used. The amino acid can be recovered by neutralization or acidification and solvent displacement. Since the amino acid is so highly soluble in water, it is preferably in situ, ie without isolation, N-aminocarbonylated. Thus, the aqueous reaction mixture containing the amino acid is simply neutralized, preferably slightly acidified, and with an excess of alkali metal cyanate

treated. The resulting Ureidoderivat (4) is then easily precipitated by acidification.

The efficiency of the overall process of 6-fluoro-4-chromanone to sorbinil is obtained by recovering crude enantiomer of the sorbinil precursor from mother liquors, preferably also recovering the amine release agent using standard techniques of basification and extraction, returning the enantiomeric material to 6 -Fluor-4-chromanone, greatly improved by the methods described later.

Further, the invention otherwise adds undesirable and unavoidable by-products in the synthesis of sorbinil to the production of additional sorbinil.

When sorbinil is obtained by optical resolution of racemic (RS) -S-fluorospiro [chroman-4,4'-imidazolidine] -2 ', 5'-dione (3), i. H. as the enantiomeric salt with an optically active amine {e.g. Brucine, (-) - 3-aminomethyl-pinane, supra), the enantiomer of sorbinil, i. H. R-6-fluorospiro [chroman-4,4'-imidazolidine] -2 ', 5'-dione (7), in one of the sorbinil at least equivalent yield. The by-product, the R-isomer, is generally first obtained as a diastereomeric salt (which usually also contains some of the sorbitan salt). The recovered diastereomeric salt can be used directly in the recovery process according to the invention, preferably with simultaneous recovery of the optically active amine. Alternatively, the enantiomeric salt is converted to the free acid form (7), which usually also contains racemate (3), e.g. by simply slurrying in excess aqueous mineral acid or by elution from a suitable basic ion exchange resin and the following. Matching with acid; the free acid form is then used in the process according to the invention.

When sorbinil is obtained by optical resolution of racemic (RS-) -6-fluoro-4-ureidochroman-4-carboxylic acid, the

R isomer obtained in a s-isomer (sorbinil precursor) at least equivalent yield. Again, the by-product is generally recovered first as the diastereomeric salt (which usually contains some S-isomeric salt). The latter R isomer or its mixture is (i) used directly in the process of the present invention, preferably in the recovery of the optically active amine, (ii) by simple slurrying in mineral acid or contacting with basic ion exchange resin and subsequent contacting with acid in the Acid form (8), usually contaminated with \ racemate (4), then used in the process of the invention, or (iii) converted to the hydantoin (7), i. H. the enantiomer of sorbinil, usually containing racemate (3), then used in the process according to the invention.

The first stage of the recovery process is the hydrolysis of the hydantoin (7), the hydantoin mixture (7) and (3), the ureido acid (8) or the ureido acid mixture (8) and (4) or a cationic salt thereof to R-4. Amino-6-fluoro-chroman-4-carboxylic acid or a mixture of this .R-amino acid and the racemic amino acid (2). The hydrolysis takes place in the presence of an aqueous-inorganic base (for example an alkali metal or alkaline earth metal hydroxide, such as NaOH or Ba (OH) .beta.). When the hydantoin is the starting material, Ba (OH) - is the preferred base. When the ureido acid is the starting material, NaOH is the preferred reagent. In each case, the hydrolysis is carried out with heating to 75 to 130 C (if necessary, under pressure). Extremely convenient is the reflux temperature of the Reaktiönsgemischs, which is generally in the range of 100 b

 the dissolved substances.

in the range of 100 to 110 ⁰ C, depending on the Mo concentration

If desired, the amino acid can be recovered, e.g. By adjusting the pH to the isoelectric point (near neutral) and filtering or extracting into a water immiscible organic solvent. Preferably, however, the amino acid is used without isolation in the subsequent chlorination step.

When the starting material introduced into the basic hydrolysis step is a salt of an optically active amine, the amine is generally depleted during the hydrolysis step by extraction into a water-immiscible organic solvent such as methylene chloride, chloroform, toluene or ethyl acetate, preferably 25-50 ⁰ C, ie, before or after heating to 75-130 ^° C, most preferably before heating to minimize side reactions with the optically active amine.

The second stage of the recovery process involves the chlorination of the overall transition-state amino acid to a mixture (a) of 6-fluoro-2-chromanone and 6-fluoro-2-chloroiminochroman. The second stage is generally carried out directly on the aqueous amino acid from the first stage with optionally pH control in the. second stage. In any case, even when carried out on isolated amino acid, the second stage, as the first stage, in aqueous media.- The temperature is not critical, z. B. are O to. 5 0 C satisfactory. For convenience, room temperatures (eg 17 to 27 ^° C.) are preferred. The product mixture is simply filtered from the aqueous reaction mixture, preferably at high pH

^ (8.5 to 10.5) isolated,

The ratio of ketone and chlorimine in the mixture formed in the second stage depends on the chlorinating agent and the conditions of the chlorination. Among a group of preferred conditions, namely, N-chlorosuccinimide as a chlorinating agent having a pH controlled between 4 and 5.5, the ketone predominates, especially if the amino acid is not isolated and is a mixture derived from the hydantoin Cmlt barium hydroxide base , On the other hand, under one. second group of conditions using sodium hypochlorite as the chlorinating agent (without pH adjustment) outweighing the chloroimine, especially if the amino acid is not isolated and is a mixture derived from ureido acid in strong aqueous sodium hydroxide.

The third step of the recovery process is the hydrogenation of the ketone / chlorimine mixture (9), carried out under (aqueous) hydrolysis conditions, usually with an added, reaction-inert, water-miscible organic solvent, to help produce at least a portion of the mixture ( 9) in solution. Methanol is the preferred solvent for this purpose, generally added not just prior to hydrogenation but after hydrogenation to help separate the purified product from insoluble catalyst.

The hydrogenation is via a hydrogenation catalyst, preferably a noble metal catalyst, such as platinum, palladium, rhenium, rhodium and ruthenium, either of the supported or unsupported type, including the known catalytic compounds thereof, such as oxides, chlorides, etc., examples of suitable catalyst supports Carbon, silica and barium sulfate. The catalysts may be preformed or formed in situ by prereduction of a suitable salt of the catalytic compound. Examples of preferred catalysts are. 5% Pd / C, 5% Pt / C, 5% Rh / C, platinum chloride, palladium chloride, platinum oxide and ruthenium oxide. Palladium, especially Pd / C, is the most preferred catalyst for the present invention. Process, since complete conversion of the chloroimino compound is easily achieved under mild conditions.

The temperature ist.keine critical variable in the hydrogenation, temperatures in the range of 0 to 100 ⁰ C are generally satisfactory. Conveniently, ambient temperature is preferably (17 to 27 ⁰ C), since at this temperature the hydrogenation at a reasonable rate and with a reasonable amount of catalyst takes place, and with heating or cooling associated costs are avoided. The pressure is also not critical, with pressures in the range of subatmospheric pressure up to 100 bar (at) or above being satisfactory. Since the

Required equipment is much less expensive and costly, moderate pressures (2 to 8 bar (at)) are preferred.

Bas 6-fluoro-4-chromanone recovered by the recovery process according to the invention is suitable for the re-conversion into sorbinil by the method of Sarges (supra) or the methods described above.

The present invention is illustrated by the following examples. It should be understood, however, that it is not limited to the specific details of these examples. All temperatures are given in ⁰ C. Unless specified, temperatures are room temperatures and solvent removal is done in vacuo.

embodiments example 1 RS-4-amino-6-fluorochroman-4-carboxylic acid

A stirred slurry of RS-6-fluorospiro [chroman-4,4'-imidazolidine] -2 ', 5'-dione (78 g, 0.33 mol) and Ba (OH) ₂ .8H ₂ O (2 08.3 g, 0.66 mol) in 585 ml H ₃ O was slowly heated to reflux for 3 hours and refluxed for 16 hours. The slurry was cooled to 80 ° and powdered (NH ₃ CO ₃ (78 g) was added portionwise over 5 minutes., Moderate foaming was noted, and after stirring for 1.5 hours at 8 °, the mixture was cooled to 60 ° and filtered Diatomaceous earth was filtered with 2 x 100 ml of hot H 2 O. To wash, filtrate and wash were concentrated to 2 00 ml after combining and allowed to stand overnight 2.-propanol (600 ml) was added and the mixture was warmed to 70 ° The hot solution was treated with charcoal, filtered through diatomaceous earth, and washed with hot 1: 1 H ₂ 0/2-propanol, and the filtrate and washings were made to be 200 ml after being purified concentrated and water with 3 χ 3 00 ml fri-

2-propanol. The resulting thick slurry was mixed with 2 00 ml of additional 2-propanol. cooled, cooled to 5 °, granulated for 0.5 hours, filtered and air-dried to give title product, 63.6 g, 91.2%, mp 252-253 ° (dec.).

Example 2 RS-6-fluoro-4-ureidochromane-4-carboxylic acid

Method A

Title product from the previous example (21.1 g, 0.1 mol) was slurried in 250 ml H ₃ O. KOCN (16.2 g, 0.2 mol) was added portionwise over 2.5 minutes. The almost perfect solution was stirred at 23 for 22 hours. the pH increased from 6.8 to 9, T and complete solution occurred. Concentrated HCl (19.0 mL) was added over 1 hour, with the temperature at. 25 to 29 ⁰ C was held. The resulting slurry was granulated for 1 hour (pH 3.2 to 3.5), and the title product was recovered by filtration washing with 150 ml of H ₂ O, partially in air and then dried at 50 to 55 hours in vacuo, 2 0, 0g, 79%.

Method B

The same starting I-midazolidine as used in the previous example (47.2 g, 0.2 mol) and NaOH pellets (28 g, 0.7 mol) were combined in 600 mL H 2 O and heated to reflux for 4 hours , The reaction mixture was cooled to 24 and the pH lowered from 11.8 to 5.0 with 6 η HCl. At pH 8, gas evolution was noted. After stirring the slurry at pH 5 for 2 minutes, KOCN (32.5 g, 0.4 mol) was added over 2 minutes, the mixture stirred for 20 hours, and a small amount of solids filtered off and washed with 50 ml of water. The filtrate and washings were adjusted to pH 4.0 after combining with 6 η HCl. Precipitated title product was recovered by filtration, washed with warm water

- 18 and air-dried, 39.7 g (78%), mp 198-199 ° (dec.),

Alternatively, the NaOH hydrolysis step was carried out at 118 ° C and 1.89 bar gauge pressure (27 psig) for 18 hours. Further reaction with "KOCN and isolate as immediately before gave title product, 38.8 g (76.4%) m.p. 199 to 200 ° (decomp.)

Alternatively, KOH (26.4 g, 85%, 0.4 mol) replaced NaOH at a reflux time of 22 hours. Reaction with KOCN and isolation as immediately above gave title product, 36.8 g (72.4%), mp 198-199 ° (dec.).

Example 3 D- (+) - (1-Phenethyl) ammonium S-6-fluoro-4-ureidochromane-4-carboxylate

Title product of the previous example (10.0 g, 39.4 mmol) was slurried in 4 00 ml of methanol at 45 + 5 for 1 h. Over 4 minutes, 4.87 g (40.1 mmol) of D- (+) - (1-phenethyl) -amine in 45 ml of methanol was added to the resulting thin slurry, giving a solution. The bath was removed, the mixture was cooled slowly to room temperature, the mixture granulated for 16 hours and crude title product recovered by filtration and dried at 60 in air, 6.4 g 86.6%, mp 0.2 to 210 ° [alpha ] ^ ³ = + 54.3 ° (c = 0.3, methanol). Crude title product, 6g, was reslurried in 180 mL of methanol at 40 to 50 ° C for 1 h, cooled to room temperature, granulated for 3 hours, filtered and air dried to give purified title product, 4.4 g, mp 214 to 216 °. [alpha] _D = + 69 ° (c = 0.3 in methanol), 73.3% recovery, overall yield 63.5%.

The mother liquor from the crude title product was concentrated to a mixture consisting mainly of D - (+) - (1-phenethyl) ammonium R 6-fluoro-4-ureidochromane-4-carboxylate together with title product, 8.3 g. mp. 198-200 ⁰ C, [alpha] ^ ⁵ = -35.4 °

(c = 0.5, methanol), suitable for recycling to 6-fluoro-4-chromanone. According to one possibility, this salt mixture is partitioned between ethyl acetate and water, the pH being first adjusted to 10. The ethyl acetate layer is separated and, if appropriate, active amine is recovered by evaporation. The pH of the aqueous phase is then adjusted to 1 to 2 with hydrochloric acid, extracted with fresh ethyl acetate. , The organic phase is washed with additional small portions of water, dried (over MgSO 4) and evaporated to a mixture of R- and RS-6-fluoro-4-ureidochroman-4-carboxylic acid.

Example 4

sorbinil

Title product of the preceding Example (4.3 g, 11 iriMol) was slurried in 30 ml glacial acetic acid for 2 hours at 93 ⁰ C, where after the first 15 minutes, a solution. The mixture was cooled to 6 ° and concentrated to 10 ml. Warm water (21.5 ml, 50 °) was added, resulting in a slurry with a pH of 3.5. After 5 minutes, the pH was adjusted to 4.5 with 4 ml of 4 N NaOH (temperature now 28 °) and the mixture was cooled to 20 ° over 30 minutes. Filtration gave directly relatively clean sorbinil, 2.35 g, 90.3%, mp. 238-241 ⁰ C ,. [alpha] ^ ⁵ = + 52.7 ° (c = 1, methanol). Sorbinol was purified by dissolving 2.2 g in 27.4 ml of boiling acetone, clarified by hot filtration, and the mother liquor concentrated to 13 ml. The resulting slurry was diluted twice slowly with 17.2 ml of hexane and concentrated to 13 ml. Filtration and air drying yielded purified sorbinil, · 1.924 g, 87.5%, mp 239.5 to 242.5 °. [alpha] ^ ⁵ = +54.5 (c = 1, methanol).

Relatively clean sorbinil, 56.2 g, mp 237 to 241, / alpha / - = + 52.3 ° (c = 1, methanol), also prepared in 89.8% yield from title product of the previous example, was prepared in 700 dissolved in boiling acetone, clarified by filtration and

concentrated to 300 ml. Hexane (400%) was added slowly and the mixture was again concentrated to 3 00 ml. Hexanzugabe and concentration were repeated, yielding purified title product, vacuum dried at 40 ⁰ C for 18 hours ,. 54.9 g, 97.7%, mp 236 to 241 ° _; [alpha] ^ ⁵ = + 53.4 ° (c = 1 in methanol).

Example 5 L - (-.) - Ephedrine salt of S-6-fluoro-4-ureidochromane-4-carboxylic acid

Method A

Title product from Example 2 (35.6 g, 0.14 mol) was slurried in 1.07 acetone, stirred at reflux (59 °) for 30 minutes, and cooled to 54 °. L - (-) - ephedrine (24.4 g, 0.148 mol) was added in one portion. The slurry was diluted and almost a solution resulted. After less than 2 minutes at 55 °, crystallization began rapidly. The slurry was refluxed for 2 hours cooled to '40 ⁰ C and sugar-like. Crystals of the crude title product were obtained by filtration, 26.1 ι methanol).

m., 26.1 g, m.p. 204 ° (dec.) j [alpha] ^ ⁵ = + 37.0 ° (c = 1,

The mother liquor gave at room temperature a second crop of solid, 1.3 g, mp 180-185 ° (dec.); [alpha] _D = 0 ° (c = 1, methanol).

Concentration of the mother liquor gave foamy solids, 32.9 g, mp 72-90 ° (dec.); [alpha] ^ ⁵ = -55.7 ° (c = 1, methanol)

The first yield solid (25 g) was reslurried in 250 ml of refluxing acetone, recovered after cooling to 40 °, 24 g; Schm. 205 ° (decomp.); [alpha] _Q = +38.2 (c = 1, methanol). Evaporation of the mother liquor to dryness gave 1.2 g, mp 90-110 ° (dec.); [alpha] ^ ⁵ = + 31.4 ° (c = 1, methanol).

Once resuspended solids (13 g) were reslurried in 260 ml of refluxing acetone, recovered after cooling to -45, 11.7 g, [alpha] = + 39.3 (c = 1, methanol). Concentration of the mother liquor yielded a further 1.1 g of solids. '-

Method B

Title product from example 2 (100g) was stirred at reflux (65 °) in 374ml methanol for 3 minutes, then cooled to 59 °. Water (7.42 ml) and L - (-) - ephedrine (68 g) were added, resulting in a heavy precipitate. The slurry was refluxed at 66 ° for 45 minutes / cooled to 27 and highly purified title product recovered directly by filtration, 70.4 g, [alpha] ⁵ = + 44.36 ° (c = 1.04 in methanol). The filtrate was concentrated to give the crude diastereomeric salt, L - (-) - ephedrine R-6-fluoro-4-ureidochromane-4-carboxylate, 116.3 g.

Example 6

sorbinil

Once again slurried title product of the previous example (9.6 g, prepared according to method A) and 68 ml of glacial acetic acid were heated for 1 hour at 95 ⁰ C, concentrated in vacuo at 6 0 to 20 g of oily residue, with 50 ml H "O at 60 ° and then diluted 50 ml H ₂ O at 10 °. The resulting slurry was made up with 4 η NaOH of pH 3. 4.5 adjusted to raw

¹ D

Sorbinil, 4.7 g, mp 234-240 °; [alpha]. + 50.5 ° (σ = 1, methanol). This crude sorbinil, 4.0'g, was dissolved in 60 ml of boiling, absolute ethanol, clarified by filtration, cooled to 24 ° and purified sorbinil recovered by filtration, 2.0 g, mp 240.5 to 243, 0 °, [alpha] = + 55.4 ° (c = 1, methanol).

The highly purified title product of the previous example (10 g, prepared according to method B) was purified by the same method.

converted into highly purified sorbinil, 4.93 g, mp,

2 ^[

¹ D

240 to 242 ° ;. [alpha];? ⁵ = + 54.7 ° (c = 1, methanol).

Example 7 R- and RS-6-fluoro-spiro [chroman-4,4'-imidazolidine] -2 ', 5'-dione

Following the procedure of Example 4, D - (+) - 1- (phenethyl) -amine salt of R- and RS-6-fluoro-4-ureidochroman-4-carboxylic acid is converted to title product.

Example 8 Crude 6-fluoro-4-chromanone from sorbinil enantiomer and racemate

Left-handed (R) and / or racemic (RS-) 6-fluoro-spiro [chroman-4,4'-imidazolidine] -2 ', 5'-dione (100 g, 0.423 mmol) was dissolved in 750 ml Slurried H ₃ O Ba (OH) ₂ -8H ₃ O (267.0 g, 0.846 mol) was added and the resulting thin slurry was refluxed for 48 hours. The resulting heavy suspension was cooled to 60 to 65 ° C, and (NH 3, COt (100 g, 0.876 mol) was added.) The slurry was stirred for 30 minutes and washed at 5 ° to 55 ° with 300 ml of warm water to wash the collected The filtrate and washings, after combining with hydrochloric acid, were adjusted from pH 8.5 to 4.5-5.0. To the acidified solution, N-chlorosuccinimide (57.0 g, 0.427 mol) was added portionwise over 5 The resulting slurry was stirred for 17 hours at room temperature, then for 1 hour at 15 ° C. Solids were filtered off, taken up in GH ₂ Cl ₂ , treated with charcoal and CH ₂ Cl ₂ with hexane to hexane to a pot temperature of 68-6 9 ° and a final volume of 400-500 ml, crystallization occurred, and after cooling and digesting for 1 hour at 20-25 °, purified title product was filtered off, 5 0.2 g, with the physical Characteristics of the known material ..

Thus produced title product contains 6-fluoro-4-chloroiminochroman as impurity. The latter interferes with the further use of the title product in the synthesis of additional sorbinil. The impurity is removed (converting it to the desired 6-fluoro-2-chromanone) according to the following example.

Beispiel.9 Purification of crude 6-fluoro-4-chromanone by hydrogenation

Crude δ-fluoro-4-chromanone containing 6-fluoro-4-chloroiminochroman as impurity (5.0 g), 5% Pd / C (50% water wet, 0.25 g) and 1: 1 H ₂ OiC ₂ H ₅ OH (100 mL) was combined, and the mixture was hydrogenated at 3.15 bar (45 psig) hydrogen for 2 hours whereupon TLC on silica gel (with toluene / methyl ethyl ketone / acetic acid 5: 2: 1 as eluent) Lack of faster migrating chlorimine (R ^ 0.8) in 6-fluoro-4-chromanone (R, 0.7). The reaction mixture was diluted with 100 ml of methanol (to completely dissolve other solids as catalyst), the catalyst recovered by vacuum filtration on a diatomaceous earth cushion, and the filtrate concentrated in vacuo to 50 ml (from a 45 ° water bath) to 5 Cooled, granulated for 15 minutes and filtered to give purified title product, 2.65 g, mp 108-112. DC as stated above.

Example 10 R- and RS-6-fluoro-4-ureidochromane-4-carboxylic acid . . '

Method A

Recovered D - (+) - (1-phenethyl) ammonium R-6-fluoro-4-ureidochromane-4-carboxylate (which also contained, to a lesser extent, the corresponding D-ammonium-S-carboxylate salt), 32.3 g was combined with 215 ml of 1 N HCl and 21 hours at 16 to

23 ° stirred. Title product was recovered by filtration, 20.6 g, 94%, Schrap. 195 to 198 ° (Zers.).

Method B

A column with a 5 0 ml volume previously used ion exchange resin (Amberlite IRA 900) was., Slowly successively with 250 ml of deionized H ₃ O, 25 0 ml 1 η NaOH, 25 0 ml N ^ -purged H-jO and 250 ml R purged with rinsed methanol. Crude enantiomeres. Salt (10 g) in 50 ml of methanol was added to the column, eluted with an additional 100 ml of methanol, and the eluent was concentrated in vacuo to give recovered ephedrine, 0.019 9 mol, by titrimetric analysis with 0.1 N HCl in methanol. The column was then eluted with 1.50 ml of methanol containing 4.4 g of dry HCl and finally with 150 ml of fresh methanol. The latter methanol-HCl and methanol elution amounts were combined and concentrated in vacuo to give enantiomeric (R) and racemic (RS) 6-fluoro-4-ureidochroman-4-carboxylic acid, 5.86 g.

Example 11

Crude 6-fluoro-4-chromanone from R- and RS-6-fluoro-4-ureidochranane .4-carboxylic acid

Title product from the previous example ("100 g) was slurried in 475 ml H ₂ O. 50% NaOH, 32 g, was added causing incomplete dissolution, the mixture was heated to a pot temperature of 10 ° C over 40 minutes (reflux It was refluxed and the mixture was cooled for a further 18 hours, the pH was 9.6 and TLC indicated incomplete reaction, the pH was adjusted to 1 2 with 13.8 g of 50% NaOH, The mixture was refluxed for 2.5 hours, at which time TLC on silica gel (toluene / methylethyeton / acetic acid 5: 2: 1 as eluent) no more than traces of starting material (R _f 0.5) with a high content of Intermediate R- and RS-6-fluoro-4-aminochroman-4-carbon

acid (FU 0.0) indicated. The reaction mixture was cooled to 20 ° and adjusted to pH 4.5 with concentrated HCl while maintaining the temperature below 3.degree., With the formation of a precipitate. N-chlorosuccinimide (53 g) was added over 15 minutes maintaining the temperature below 30 ° and the pH at 4.0 to 4.5 by the concurrent addition of 7 ml of 50% NaOH. The reaction mixture was stirred for 1 hour at 25 ° C whereupon the pH was 5.2, and TLC (above system) indicated complete conversion of the intermediate amino acid into products. The pH was then adjusted to 9.6 with about 27 ml of 50% NaOH, the basic slurry granulated for 2 hours at 20 ° and the title product recovered by filtration, 50.0 g, mp 55-58 ° (partial), 65-50 75 ° (complete but melt not clear); TLC (above system) showed title product (R _f 0.7) with 6-fluoro-4-chloroiminochroman (R, -0.8).

Alternatively, D- (+) - (1-phenethyl) ammonium-R-6-fluoro-4-ureidochroman-4-carboxylate, which contains a small proportion of the corresponding D-ammonium-S-carboxylate, is used in the process according to the invention. In the first stage of the process, the salt is partitioned between the 5% NaOH and an equal volume of CH ₂ Cl. The aqueous phase is washed twice with a third volume of CH 2 Cl 2. The organic layers are combined and concentrated to give D - (+) - (1-phenethyl) amine which is suitable for recycle. The aqueous phase is drawn through the remainder of the process of the present invention to provide title product.

Example 12

6-fluoro-4-chloroiminochromane from R- and RS-6-fluoro-4-ureidochroirane

The preceding example was repeated on a tenth scale to give the intermediate R- and RS-6-fluoro-4-aminochroman-4-carbon

Example) with 15 wt .- / wt .-% NaOCl (48.2 ml) at 'a temperature of 2 0 to 30 °. The mixture was 3.5 hours

Stirred at 20 to 25, whereupon TLC (system, as in the previous example) conversion \ orx amino acid into. virtually pure title product, with little trace of 6-fluoro-4-chromanone indicated. Title product was recovered by filtration, 3.8 g, RC 0.8 in the above system.

Example 13

6-fluoro-4-chroman from chlorimine

Title product of the previous example (3.6 g) and 5% Pd / C, 50% water wet (0.18 g on dry basis) were combined in 72 mL of methanol / water, 9: 1. The pH was adjusted to 2.0 with concentrated HCl and the mixture hydrogenated at 3.7 to 4 bar (40 to 45 psig) of hydrogen for 2 hours. Catalysts were filtered through a diatomaceous earth pad. The filtrate showed only title product by TLC (R.p. 0.7 in the system of the immediately preceding examples), easily recovered by concentration in vacuo. TLC indicated that some product remained in the catalyst cake, which is easily recovered by re-slurrying the catalyst cake in methanol.

Example 14 Sorbinil via its (-) - 3-aminomethylpinan salt

(-) - 3-Aminomethyl-pinane-HCl, 9.5 g, (46.6 mmol), ethyl acetate (186 ml) and 1 N NaOH (93 ml) were stirred vigorously for 10 minutes. The organic layer was separated, washed with 1 χ 93 mL H ₂ O, dried (over MgSO ₄ ), and concentrated to give (-) - 3-aminomethylphenyl, free base, an oil, 1.15 g (m.p. 99%), [alpha] ^ ⁵ = -54.85 ° (c = 1 in methanol), which was then dissolved in 20 ml of methanol.

Racemic 6-fluoro-spiro [4H-1-benzopyran-4,4'-imidazolidine] 2 ', 5'-dione (10.0 g, 42.3 mmol) was dissolved in 214 ml of 2-propanol and

Dissolved 194 ml of methanol, heated to reflux, and the above solution of the amine was added, giving a clear solution at the reflux temperature of 71 °. The solution was cooled slowly (crystallization started at 27 °) and stirred at room temperature for 6 hours. The crude (-) -3-aminomethylpinan salt of sorbinol was recovered by filtration and dried in vacuo at 40 ° C, 6.81 g, mp 127.5 to 196 ° (dec.), [Alpha] ^ ⁵ = -8, 2 ° (c = 1 in methanol). Stage yield 79.6%. The mother liquor thereof is concentrated to dryness to give crude (-) - 3-aminomethylpinane salt of the enantiomer of sorbinil, the major impurity being (-) - 3-aminomethyl-pinane salt of sorbinil.

Crude sorbitan salt (6.7 g) was dissolved in 80.4 ml of 1: 1 methanol / isopropanol at reflux, cooled slowly to room temperature, and the resulting solids were granulated for 2 hours. Purified salt was collected by filtration with 4 ml of 1: 1 methanol / isopropanol for washing and dried in vacuo at 40 ° C, 4.42 g, mp 119-208 ° (dec.), [Alpha] ^ ⁵ = +3, 9 ° (c = 1 in methanol). Stage yield: 66%.

Purified salt (4.33 g, 10.7 mmol) was partitioned in 107.5 mL of ethyl acetate and 53.8 mL of 1 N HCl. The organic layer was separated, with 1 χ 54 ml 1 η HCl ,. Washed 1 × 54 ml of H 2 O and 1 × 54 ml of brine, dried (over MgSO 4), filtered, concentrated to a slurry in vacuo, brought to a final volume of 12 ml with 3 × 50 ml of ethyl acetate, granulated for 3 hours, filtered and dried in vacuo at 40 ° to give sorbinil, 2.18 g, mp 234-242 °, ialphajQ ⁵ = + 51.2 ° (c = 1, methanol). Stage yield: 86.2%. Alternatively, the dried organic layer is extracted with one equivalent of 1 N NaOH. The extract is separated and lyophilized to give the sodium salt of sorbinil.

The above aqueous layers of sorbinol recovery were

combined (226 ml), combined with 113 ml CH ₉ Cl and. the pH is adjusted to 10.0 with 25% NaOH. The aqueous layer was separated and extracted with 55 ml of fresh CH ₉ Cl ₉ . The CH ₂ Cl ₂ layers were combined, concentrated in vacuo to 60 ml, washed with 1 × 30 ml H ₉ O, dried (over MgSO ₄ ), and concentrated to give recovered (-) - 3-aminomethylpinane, an oil, 1 , 58 g, [alpha] _D = -55.5 ° (c = 1, methanol).

Sorbinil was further purified by dissolving in 20 ml of hot ethanol, to which half volume was concentrated and granulated for 4 hours at room temperature. Purified sorbinil was recovered by filtration and dried at 40 ° in vacuo, 1.82 g, mp 234-24 1.5 °. [alpha] ^ ⁵ = +53.1. Stage yield: 91%. Total yield: 41.2%.

Following the same extraction techniques as described above, the above crude (-) - 3-aminomethyl-pinane salt of the enantiomer of sorbinol is converted to (-) - 3-aminomethyl-pinane suitable for reconversion and into the enantiomer of sorbinil contaminated with racemate.

Example 15 Sorbinil via its (-) - 2-amino-2-norpinane and quinine salts

Racemic 6-fluoro-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2 ', 5'-dione (25 g, 0.106 mol) was slurried in 250 ml of isopropanol and 100 ml of methanol and heated to reflux. A solution of (-) - 2-amino-2-norpinane (14.73 g, 0.106 mol) in 15% methanol was added over .16. Minutes to the 'hot slurry. Complete dissolution occurred when about 75 ml of the amine solution had been added. The solution was held briefly at reflux and then slowly cooled to 0 to 5 ° C. The resulting slurry was granulated for 2 hours and (-) - 2-amino-2-norpinan salt of sorbinil enantiomer by filtration

recovered (with 25 ml of 1: 1 isopropanol / methanol for washing) and dried at 40 ° C in a vacuum, 18.71 g, mp 170 to 187 ⁰ C, [alphajp ⁵ = -24.3 ° (c = , Methanol). Yield 94.5% of theory.

The combined mother liquor and wash solution (515 ml), mainly the (-) - 2-amine-2-norpinan salt of sorbinil. was concentrated in vacuo to 25 0 ml and diluted with 512 ml of ethyl acetate and 256 ml of 1 η HCl. The organic layer was separated, washed with 1 × 256 ml of fresh 1N HCl, 1 × 256 ml of H ₃ O and 1 × 256 ml of brine, dried (over MgSO ₄ ), concentrated in vacuo to 100 ml, and the residual ethyl acetate was added with 3 χ 100 ml hexane distributed to a final volume of 75 ml. The resulting slurry was granulated for 2 hours and filtered to yield crude sorbinil, dried in vacuo at 4 0 ° C, 11.56 g, mp. 225-237 ⁰ C, [alpha] _D = + 28.5 °. Stage yield: 92.5%.

Crude sorbinil (11.44 g, 48.4 mmol) was slurried in 137 mL isopropanol and heated to reflux. A solution of quinoline trihydrate (18.3 g, 48.4 mmol) in 34.3 mL of methanol was added over 7 minutes, giving a clear solution, and refluxed for an additional 5 minutes. Die.Lösung was cooled slowly to 0 to 5 C, granulated for 2 hours and the quinine salt of sorbinil collected by filtration and dried at 40 ⁰ C, 16.05 g, Schrap. 113 to 122 ⁰ C, (dec.), [Alpha] ^ ⁵ = -70.4 °. Stage yield: 77.9%.

In an optional step, the quinine salt of sorbinil (15.96 g) was dissolved by dissolving in 7.9 ml of isopropanol at reflux, concentration to 44 ml, slow cooling to room temperature, dilution with 20 ml of isopropanol, cooling to 0-5 ⁰ C, granulated for 2 hours, filtered and dried at 40 ° C recrystallized in vacuo, 14.38 g, mp 110.5 to 122 ⁰ C (dec.), [Alpha] ^ ⁵ = -71.0 ° ( c = 1, methanol). Stage yield: 90%.

Quinine salt of sorbinil (14.1 g, 25.1 mmol) was partitioned between 350 mL of ethyl acetate and 175 mL of 1 N HCl. The Ethylaeetatschicht was separated, washed with 1 χ 175 ml of fresh 1 η HCl, 1 χ 175 ml H ₃ O and 1 χ 175 ml brine, dried (over MgSO ₄ ), concentrated to 25 ml in vacuo, 3 χ 50 ml of ethyl acetate until to a final volume of 20 ml, cooled to ⁰ to 5 ° C., granulated for 2 hours, and sorbinil was filtered off, 4.72 g, mp 241 to 246 ° C., [alpha] ^ ⁵ = + 54.0 ° ( c = 1, methanol). Stages of prey: 80%. Total yield: 3 9.1%.

Example 16 Sorbinil via its (+) - 3-aminomethyl-pinane and quinine salts

Substituting the (-) - 3-aminomethylpinane in the first step of Example 1 for the same amount of (+) - 3-aminomethyl-pinan-HCl, the crude (+) - 3-aminomethyl-pinane salt of the enantiomer of sorbinil is treated in the same amount with the same Melting point and same optical rotation, except with opposite sign, isolated. Following the procedures of Example 2, the combined mother liquor and wash liquor containing a concentrate of the (+) - 3-aminomethylpinane salt of sorbinol is worked up to give a partially separated concentrate of sorbinil, then converted to quinine salt of sorbinil and finally to sorbinol.

Claims (7)

P.C. (Ph) 6548/6551/6569 invention claim A process for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof, characterized in that it comprises the steps of: (a) crystallizing the (-) - 3-Aminomethylpinansalzes of sorbinil from a solution of racemic hydantoin of the formula: (b) converting the aminopinane salt to sorbinil or its pharmaceutically acceptable salt. 2. A process for the preparation of sorbinil or a pharmaceutically acceptable cationic salt thereof, characterized by comprising the steps of: (a) crystallizing either the (+) - 3-aminomethylpinane or the (-) - 2-amino- 2-norpinan salt of the enantiomer of sorbinol from a solution of racemic hydantoin of the formula  NH (b) isolating a concentrate of sorbinil from the mother liquor; (c) crystallizing the quinine salt of sorbinil from a solution of the sorbinil concentrate and (d) converting the quinine salt of sorbinil to sorbinil or its pharmaceutically acceptable salt. 3. A process for the preparation of a crystalline S-6-fluoro-4-ureidochroman-4-carboxylic acid salt with D- (+) - (1-phenethyl) amine or L - (-) - ephedrine, characterized in that a racemic Compound of the formula COOH is contacted with at least one half molar amount of D - (+) - (1-phenethyl) amine or L - (-) - ephedrine in a reaction-inert organic solvent and the crystalline salt is recovered. 4. The method of item 3, further comprising cyclizing the recovered crystalline salt in glacial acetic acid to form VDn sorbinil and recovering the sorbini or its pharmaceutically acceptable cationic salt. 5. A process for regenerating purified 6-fluoro-4-chromanone from R- or a mixture of R- and RS-6-fluoro-spiro [chroman-4,4'-imidazolidine] -2 ', 5'-dione , R- or a mixture of R- and RS-6-fluoro-4-ureidochroman-4-carboxylic acid or a cationic salt thereof, characterized in that it comprises the following steps: (a) hydrolysis in the presence of an aqueous inorganic base to form an intermediate amino acid which is R or a mixture of R- and RS-4-amino-6-fluoro-chroman-4-carboxylic acid; (b) decomposing the intermediate amino acid in an aqueous solvent with a chlorinating agent to form a mixture of 6-fluoro-4-chromanone and 6-fluoro-4-chloroiminochroman, and (c) hydrogenating the mixture of 6-fluoro-4-chromanone and 6-fluoro-4-chloroiminochroman over a noble metal catalyst in an aqueous or aqueous-organic solvent to the purified 6-fluoro-4-chromanone. 6. The method according to item 5, characterized in that the purified 6-fluoro-4-chromanone from R or a mixture of R and RS-6-Fiuor spiro [chroman-4,4'-imidazolidine] -2 ', 5'-dione or a cationic salt thereof is regenerated. 7. The method according to item 5, characterized in that the purified 6-fluoro-4-chromanone from R or a mixture of R and RS ~ 6-fluoro-4-ureidochroman-4-carboxylic acid or a cationic salt thereof is regenerated ,