RU2434004C1 - Method of producing (s)-7,8-difluoro-2,3-dihydro-3-methyl-4h-[1,4]benzoxazine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (S)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]benzoxazine of formula

(S)-1. The method is realised by reacting racemic 7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]benzoxazine of formula

(I) with an acyl chloride of (S)-naproxen of formula

(II) in toluene or dichloromethane at temperature ranging from 0 to -40°C and molar ratio of compound (I) to compound (II) equal to 1:0.5. The obtained mixture is treated with hexane and recrystallised from ethyl alcohol to obtain a compound of formula

(III). Compound (III) undergoes acid hydrolysis in a mixture of acetic and hydrochloric acid at temperature 92-96°C for 8-10 hours to obtain a compound (S)-l.

EFFECT: improved method of obtaining a composition with high content of the basic substance and high enantiomeric excess.

1 cl, 3 dwg, 1 tbl, 3 ex

Description

Technical field

The present invention relates to intermediates that are useful in the preparation of antibacterial compounds, in particular the antibiotic levofloxacin, which has high antimicrobial activity; and methods for their preparation.

State of the art

Known methods for producing (S) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine ((S) -1) can be divided into two main groups.

The first group of methods includes asymmetric synthesis methods based on 1) asymmetric reduction of imines by chiral reducing agents [EP 273399. Preparation of optically active 2,3-dihydrobenzoxazine derivatives as intermediates for ofloxacin and related antibacterials / Hayakawa J., Atarashi S. ( Daiichi Seiyaku Co., Ltd., Japan) // Appl. 07/06/88 JP 86/314095, 12/25/86. 12 pp .; Atarashi S., Tsurumi H., Fujiwara T., Hayakawa J. Asymmetric reduction of 7.8-difluoro-3-methyl-2H [l, 4] benzoxazine. Synthesis of a key intermediate of (S) - (-) - ofloxacin (DR-3355) // J. Heterocyclic Chem. - 1991. - V.28. - P.329-331] and chiral catalysts based on Ir (I) complexes [JP 05246995. Preparation of optically active benzo-fused cyclic amine / Yukimoto J., Kanai K., hianaga M., Achinami K. (Daiichi Seiyaku Co ., Ltd., Japan) // Appl. 03/02/92 JP 92-44308, 09/24/93. 6 pp .; Satoh K., Inenaga M., Kanai K. Synthesis of a key intermediate of Levofloxacin via enantioselective hydrogenation catalyzed by iridium (I) complexes // Tetrahedron: Asymmetry. - 1998 .-- V.9 (15). - P.2657-2662; PCT Int. Appl. (2009) WO 2009005024. Method for producing optically active amines by asymmetric reduction of imines / Maeda S. (Hamari Chemicals, Ltd., Japan) // Appl. 06/30/2008 JP 61809]; 2) asymmetric synthesis using chiral synthons - diols [EP 322815. Propoxybenzene derivatives, their preparation and use in the preparation of benzoxazine derivatives, especially antibacterials such as ofloxacin / Fujiwara T., Ebata T. (Daiichi Seiyaku Co., Ltd., Japan) // Appl. 12/23/88 JP 87-336489, 22 pp .; EP 368410. Optically active benzoxazines and benzothiazines and a process for their stereospecific preparation / Van Zoest W.J., Marx A.F., Koger H.S., Booy J. (Gist-Brocades N.V., Neth.) // 16.05.90 EP Appl. 88/202484, 11/7/88; 56 pp .; JP 08269024. Preparation of benzoxazine derivative as intermediate for bactericides / (Korea institute of Science and Technology, S. Korea) // 15.10.96 Appl. JP 96-54702, 03/12/96; 5 pp .; Kang S.B., Ahn E.J., Kim Y., Kim Y.H. A facile synthesis of (S) - (-) - 7,8-difluoro-3,4-dihydro-3-methyl-2H-1,4-benzoxazme by zinc chloride assisted Mitsunobu cyclization reaction // Tetrahedron Lett. - 1996 .-- V.37 (52). - P.9317-9320], alanine derivatives [Bower J.F., Szeto P., Gallagher T. Enantiopure 1,4-benzoxazines via 1,2-cyclic sulfamidates. Synthesis of Levofloxacin // Org. Lett. - 2007 .-- V.9 (17). - P.3283-3286; Parai M.K., Panda G. A convenient synthesis of chiral amino acids derived 3,4-dihydro-2H-benzo [b] [1,4] thiazines and antibiotic Levofloxacin // Tetrahedron Lett. - 2009 .-- V.50 (33). - P.4703-4705] and lactic acid [RF Patent 2258069. A method for producing a benzoxazine derivative, methods for producing its intermediate and intermediate compounds / Sato K., Takayanagi Y., Okano K., Nakayama K., Imura A., Itoh M., Yagi Ts., Kobayashi Yu., Nagai T. (Daiichi Pharmaceutical Co., Ltd., Japan) // Decl. 2002105997/04, 09/07/2000; 121 p. (BI: 36/2007)].

All these methods are multistage, require difficult-to-reach starting materials, do not provide a high yield of the target product and, moreover, do not provide the possibility of obtaining benzoxazine (-S) -1 of a sufficiently high degree of optical purity. Another group of methods consists of methods for the separation of racemic benzoxazine of the formula (I) and its derivatives.

Methods of microbiological and enzymatic separation as a result of hydrolysis of racemic benzoxazine amides are described [Sakano K., Yokohama S., Hayakawa I., Atarashi S., Kadoya S. Optical resolution of (R, S) -3- (acetoxymethyl) -7.8 -difluoro-2,3-dihydro-4H- [1,4] benzoxazine // Agricult. Biol. Chem. - 1987. - V. 51 (5). - P.1265-1270; JP 02031695. Optical separation of (-) - 3-alkyl-3,4-dihydro-2H- [1,4] -benzooxazines with bacteria / Kuroda H., Miyadera A. .. Imura A. (Daiichi Seiyaku Co. .. Ltd ., Japan) // Appl. JP 88-179616, 19880719; 4 pp .; Miyadera A., Imura A. Enantioselective synthesis of a key intermediate of Levofloxacin using microbial resolution // Tetrahedron: Asymmetry. - 1999 .-- V.10 (1). - P.119-123; JP 2003 180 380. Manufacture of optically active phenoxypropanol derivatives and preparation of levofloxacin from the derivatives / Sakamoto K., Tsusaki K. (Daiichi Fine Chemical Co., Ltd., Japan) // Appl .: JP 2002-298544 20021011, 13 pp .].

Japanese Patent [JP 01261380. Resolution of 7,8-dihalo-3-alkyl-3,4-dihydro-2H- [1,4] -benzoxazines by HPLC / Kuroda H., Miyadera A., Tojo Y. (Daiichi Seiyaku Co., Ltd., Japan) // Appl. JP 88-90952, 19880413; 4 pp.] Described preparative chromatographic separation of racemic benzoxazine (I) by HPLC on a chiral stationary phase Chiralcel OD, which yields (S) -1 with an enantiomeric excess of 99.8%.

There is also known a method for optical separation of the corresponding racemic compound (I) by forming a salt with (R) - (-) - camphor-10-sulfonic acid, separating the less soluble benzoxazine salt (S) -1, followed by isolation of the target product (S) -1 from salt [EP 304684. Process for preparation of benzoxazine derivatives / Fujiwara T., Tsurumi H., Sato Y. (Daiichi Seiyaku Co., Ltd., Japan) // Appl. 03/01/89 JP Appl. 87/194017, 08/03/87; 14 pp.]. The disadvantage of this method is the very low (49.2%) optical purity of the resulting (S) -1.

One of the methods for producing the stereoisomer (S) -1 is methods based on the optical separation of the corresponding racemic compound (compound (I)) by forming diastereomeric amides with derivatives of optically active acids. For example, a method is known for separating the corresponding racemic compound (I) by forming diastereomeric amides with optically active derivatives of cyclic amino acids, separating the amide, derivative (S) -1, by crystallization and / or liquid chromatography on silica gel and alkaline hydrolysis of the latter [EP 0206283 Optically active pyridobenzoxazine derivatives and intermediates thereof / Hayakawa J., Atarashi S., Yokohama S. et al. (Daiichi Seiyaku Co., Ltd., Japan) // Appl. 86108442.4. 06/20/86; 57 pp.]. The disadvantage of this method is the insufficiently high yield of the target compound and its complexity associated with the need to use chromatography to obtain the target compound (S) -1 of a sufficiently high degree of optical purity.

Another method for producing benzoxazine (S) -1 is based on the optical cleavage of the racemate with N- (sulfonyl substituted) - (R) -proline [JP 01175975. Preparation of (S) -3-alkyl-3,4-dihydro-4H [1 , 4] benzoxazine derivatives by optical resolution with N- (substituted-sulfonyl) - (R) -proline / Fujiwara T., Yokota T. (Daiichi Seiyaku Co., Ltd., Japan) // Appl. JP 87/333340, 12.29.87; 6 pp.]. The essence of the method consists in the interaction of optically active (R) -proline (2) with arylsulfonyl chloride and subsequent treatment with thionyl chloride to form H- (sulfonyl-substituted) - (R) -proline chloride (3), the reaction of compound (3) with the racemic compound ( I) in dichloroethane in the presence of pyridine, followed by isolation from a mixture of diastereomeric amides (4) of the derivative H- (R) -prolineinyl- (S) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1 , 4] benzoxazine (5) by fractional crystallization, its alkaline hydrolysis and isolation of the target product ((S) -1) (Scheme 1). Optical purity (enantiomeric excess, e.i.) 99%.

The disadvantages of this method are: 1) the low availability of the original asymmetric cleavage reagent, N- (sulfonyl substituted) - (R) -proline, which requires its preliminary synthesis from (R) -proline, which is non-proteinogenic and, therefore, relatively expensive amino acid; 2) high consumption of optically active cleavage reagent: 1.2 mol per 1 mol of the original racemic benzoxazine (I); 3) insufficient total yield of benzoxazine (S) -1, 30.3%, based on the benzoxazine (I) taken in the reaction.

The closest in technical essence to the claimed method is a method for producing benzoxazine (S) -1 by kinetic cleavage of the racemate using acid chloride (2S) -2- (6-methoxynaphth-2-yl) propionic acid ((2S) -naproxen) - compounds (II) [JP 2000178265. Production of (S) -benzoxazme derivative and racemization of (R) -benzoxazine derivative / Chupakhin ON, Krasnov VP, Levit GL, Charushin VN, Korolyova MA, Tzoi EV, Lee HS, Park YJ, Kim MH, Kim KC (Samsung General Chem. Co, Ltd., S. Korea) // Appl. December 16, 1998, priority December 16, 1998, 10 pp.] Is the prototype.

The essence of the method is the interaction in an organic solvent of compound (II) with a racemate (compound (I)) at a molar ratio of compound (II) to compound (I) 0.5-0.6: 1.0, respectively, which leads to the formation of mixtures of diastereomeric amides - N- (2S) -2- (6-methoxynaphth-2-yl) propionyl] - (3S) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4 ] -benzoxazine (compound (III)) and N- [2S) -2- (6-methoxynaphth-2-yl) propionyl] - (3R) -7,8-difluoro-2,3-dihydro-3-methyl- 4H- [1,4] benzoxazine (compound (IV)).

The formula of the present invention indicates that the main chemical process (acylation of racemic benzoxazine (I) with acid chloride II) is carried out in an organic solvent, and in the examples of the invention it is specified that chlorine-containing solvents are meant - dichloromethane, 1,2-dichloroethane and chloroform. It is indicated that it is desirable to carry out the reaction in a temperature range of 10-40 ° C.

Obviously, the acylation reaction cannot be carried out in any organic solvent, as indicated in the claims. For example, ethyl alcohol, used as a solvent, will undergo acylation with acid chloride II, which will lead to a significant decrease in the yield of amide formed. According to our data, the use of commercial chlorinated solvents requires special preliminary cleaning of the stabilizers contained in them, most often alcohols.

A mixture of amides is treated with hexane to separate them, amide IV is subjected to acid hydrolysis by heating, the hydrolysis product of amide IV is combined with unreacted (R) -1 and racemized by heating with sulfuric acid to give I, and amide III is subjected to acid hydrolysis by heating in a mixture acetic and hydrochloric acids (the reaction temperature is not indicated either in the claims or in the implementation examples) to obtain the target product (Scheme 2).

It should be noted that according to the results of our studies, a single treatment of the mixture of amides III-IV with hexane does not allow obtaining (S, S) -amide (III) of a sufficient degree of optical purity (diastereomeric excess of not more than 99.0%), which subsequently leads to the target compound, (S) -benzoxazine ((S) -1) with a not sufficiently high enantiomeric excess (not more than 99.0%).

The objective of the invention is to increase the optical purity (enantiomeric excess) and chemical purity of the target product while maintaining a high yield and making it possible to obtain it on an industrial scale.

The problem is solved in that in the method for producing (S) -7,8-difluoro-2,3-dihydro-3methyl-4H- [1,4] benzoxazine of the formula (S) -1

the interaction of racemic 7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine of the formula (I)

,

,

with (S) -naproxen chloride of formula (II)

in an organic solvent medium, subsequent processing of the resulting mixture of amides of the formulas (III) and (IV)

hexane and hydrolysis of the isolated compound (III) with a mixture of acetic and hydrochloric acids when heated, toluene or dichloromethane is used as an organic solvent, the reaction is carried out at a temperature of 0 - (- 40) ° С with a molar ratio of compound (I) - compound (II) = 1: 0.5, and after treatment with hexane, the precipitate is additionally recrystallized from ethanol, then the isolated compound of formula (III) is hydrolyzed at a temperature of 92-96 ° C for 9-10 hours. Get the target product with a basic substance content of at least 99.9% and an enantiomeric excess (e.i.) of at least 99.8% (Scheme 3).

(S) -Naproxen is used as a substance for many anti-inflammatory and analgesic drugs and is available in significant quantities. It has been established that (S) -aproxen (II) acid chloride reacts much faster with the (S) -form than with the (R) -form of benzoxazine (1) [Charushin VN, Krasnov VP, Levit GL, Korolyova MA, Kodess MI, Chupakhin ON, Kim MH, Lee HS, Park YJ, Kim K. -C. Kinetic resolution of (±) -2,3-dihydro-3-methyl-4H-1,4-benzoxazines with (S) -naproheen // Tetrahedron: Asymmetry. - 1999 .-- V.10 (14). - P.2691-2702], therefore, in the proposed method, when the acid chloride (S) -naproxen (II) is reacted with a racemate (I) with a molar ratio (I) - (II) of 1.0: 0.5, mainly (S, S) -amide (III), and according to the results of our studies, the reaction conditions (nature of the solvent and reaction temperature) significantly affect the amount of diastereomeric excess (di) and the yield of amide III formed (Table 1). The acylation reaction should be carried out at a molar ratio (I) - (II) of 1.0: 0.5, since a change in the ratio of reagents in the direction of decreasing the amount of acid chloride II (less than 0.5) leads to a decrease in the yield of the resulting amide, and an increase in the amount of acid chloride ( more than 0.5) leads to a decrease in the content of (S, S) -amide (III) and an increase in the content of (R, S) -amide (IV) in the mixture of amides formed.

The diastereomeric excess (d.i.,%) of the resulting (S, S) -amide III is determined by HPLC on an Agilent-1100 chromatograph with a diode array detector and an autosampler (Phenomenex Luna C 18 (2) column 250 × 4.6 mm, particle size sorbent 5 μm; mobile phase acetonitrile: water 70:30; flow rate 0.8 ml / min; detection at 230 nm; retention times of (S, S) and (R, S) amides: 14.5-15.7 and 17.7-19.3 min , respectively). After appropriate treatment and isolation, by chiral phase HPLC (Knauer Smartline chromatograph; 4.6 × 250 mm column Chiralcel-OD-H, eluent - hexane - propanol-2 100: 1, elution rate 1 ml / min, UV detection at 230 nm; retention times of (R) and (S) -enantiomers of benzoxazine: 8.3-8.6 and 10.3-10.8 min, respectively), determine the enantiomeric excess (e.i.,%) of unreacted (R) -1. This allows you to calculate the value of the degree of conversion of the original racemate I (C,%):

and selectivity factor (s), which is the ratio of the reaction rate constants of the individual enantiomers:

[Kagan H.B., Fiaud J.C. Kinetic resolution // Topic Stereochem. - 1988. - V.18. - P.249-330]. Indicators C and s characterize the efficiency of the kinetic separation process.

Table 1. The effect of acylation conditions on the stereochemical results of the kinetic separation of racemic benzoxazine (I) by acid chloride II.

Acylation Conditions Diastereoselectivity The degree of conversion,% S selectivity factor Solvent T, ° С Reaction time, h (S, S) -amide (III), d.i.,% (R) -1, e.i.,% tetrahydrofuran +20 24 79.0 dimethylform
mid +20 24 39.0 benzene +20 24 79.4 77.6 49 twenty toluene +20 6 85.3 74,4 47 28 toluene 0 6 85.9 59.5 41 24 toluene -twenty 6 92.3 59.7 39 45 toluene -40 6 93.7 58.5 38 57 dichloromethane +20 6 80.0 74.0 48 twenty dichloromethane 0 6 79.0 80.6 fifty 21 dichloromethane -twenty 6 82.8 78,4 49 21

As can be seen from the data in Table 1, the diastereoselectivity of acylation of racemic benzoxazine (I) with acid chloride II substantially depends on the nature of the solvent. The highest values of diastereoselective excess (S, S) -amide III are observed in benzene, toluene and dichloromethane. A decrease in the reaction temperature leads to an increase in the diastereoselectivity of the acylation (the selectivity factor reaches 57 in toluene at minus 40 ° С) with a slight decrease in the degree of conversion of the initial racemate. Since benzene has a freezing point of + 5.5 ° C, in this application we propose to use toluene or dichloromethane as solvents, and carry out the acylation reaction at a temperature of 0 to minus 40 ° C to ensure high optical purity (diastereomeric excess) and yield (S, S) -amide III.

A mixture of amides (III) and (IV) resulting from kinetic separation in a ratio of 93: 7 to 90:10 is treated with hexane and (S, S) -amide III is obtained with a basic substance content of about 98.0% and a diastereomeric excess of about 99 , 0%. An additional stage of recrystallization of the obtained compound from ethyl alcohol leads to the production of pure (S, S) -amide III (the content of the basic substance is at least 99.9% and the diastereomeric excess is at least 99.9%), which is subjected to acid hydrolysis when heated in hydrochloric and acetic acids. The total yield of (S, S) -amide III is from 72 to 77%, counting on acid chloride II.

Hexane mother liquors obtained after treatment of the amide mixture and containing mainly (R, S) -amide (compound IV) and (R) -benzoxazine ((R) -1) are evaporated, the residue is subjected to acid hydrolysis to isolate chiral "Ballast" - (R) -benzoxazine ((R) -1), which can be returned to the process by racemization when heated in sulfuric acid.

Usually, the hydrolysis of amides proceeds with the cleavage of the N-acyl bond, and the starting acid and amine (or its salt) are regenerated. Since the first stage of hydrolysis is nucleophilic addition at the carbonyl group, and amines are a poor leaving group, these reactions often proceed slowly. Hydrolysis proceeds more easily both in alkaline conditions, where there is a strong nucleophile HO ^- and in acidic conditions, where protonation of the substrate promotes a nucleophilic attack with water and cleavage of the amine, in which case hydrolysis is carried out by heating. It should be noted that in the case of chiral compounds during hydrolysis under rather severe conditions (alkaline or acidic environment, heating) there is a danger of racemization of the target compounds.

Our studies (special attention was paid to both the optical purity (enantiomeric excess) of the target compound - (S) -benzoxazine (S) -1 and its chemical purity (content of the main substance)) showed that acid hydrolysis at temperature is optimal from +92 to + 96 ° C for 9-10 hours. The yields of the target compound of high optical (e.i. more than 99.8%) and chemical purity (content of the main substance of more than 99.9%) at this stage are from 85 up to 87%.

An increase in the duration of hydrolysis and an increase in the reaction temperature leads to a noticeable racemization and a decrease in the optical purity of the target compound, while a decrease in the hydrolysis temperature and a decrease in the reaction time lead to a decrease in the yield of the target compound due to the incompleteness of the process.

Obtained according to the developed scheme, (S) -benzoxazine (S) -1 does not require additional purification.

Since the acid chloride of (S) -naproxen, (S) -2- (6-methoxynaphthyl-2) propionyl chloride (compound II) is not stable during storage, it is prepared immediately before the acylation step as follows: suspension (S) - naproxen in benzene is added at room temperature with stirring, oxalyl chloride; the reaction mass is stirred for 3-4 hours at room temperature until a clear yellow solution is formed, then evaporated to dryness under reduced pressure; hexane is added to the obtained residue, the suspension is cooled to minus 18 ° C and left at this temperature for 2-3 hours; the precipitate obtained is filtered off and washed with hexane; after drying, compound II is obtained in the form of colorless crystals (melting point 96 ° C). ¹ H NMR (CDCl ₃ ) δ, ppm: 7.78-7.10 m (6H, arom.); 4.25 q (1H, CH, J = 6.9 Hz); 3.92 s (3H, OCH ₃ ); 1.67 d (3H, CH ₃ , J = 6.9 Hz).

Example 1:

Preparation of N - [(2S) -2- (6-methoxynaphth-2-yl) propionyl 1-7,8-difluoro-2.3-dihydro-3 (S) -methyl-4H- [1,4] benzoxazine (III).

To a solution of 30.0 g (0.162 mol) of (RS) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine in 410 ml of toluene was added with stirring at a temperature of 0 ° C. dropwise a solution of 20.1 g (0.081 mol) of compound II in 400 ml of dichloromethane. The reaction mass is stirred for 6 hours at 0 ° C, then washed with water (3 times 150 ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvent and drying in vacuo, the obtained residue was stirred in 500 ml of hexane at room temperature for 2 hours. The resulting suspension is cooled to minus 18 ° C and left at this temperature for 16 hours. The precipitate is filtered off in vacuo, washed on the filter 2 times with 50 ml of chilled hexane. After drying in air at room temperature, 24.2 g (75%) of compound III are obtained with a diastereoisomeric excess (di) 99.0% (HPLC: Agilent 1100 chromatograph, Phenomenex Luna C 18 (2) column 250 × 4.6 mm ; mobile phase acetonitrile: water 70:30; flow rate 0.8 ml / min; detection at 230 nm; retention times of (S, S) and (R, S) amides: 14.5-15.7 and 17.7-19.3 min). The resulting compound was recrystallized from 220 ml of ethanol to obtain 24.1 g (75%) of compound III as colorless crystals with a diastereoisomeric excess (di) of 99.9%.

The melting point is from 114 to 116 ° C.

[α] _D from +72.5 to +73.5 (C 1.4; CHCl ₃ ).

¹ H NMR (400 MHz, DMSO-d ₆ , 100 ° C) δ, ppm: 7.77-6.84 m (8H, arom.); 4.85 qdd (1H, C ³ H-benzoxazine, J = 6.8; 3.0 and 1.6 Hz); 4.52 q (1H, CH-naproxen, J = 6.8 Hz); 4.22 dd (1H, C ² H _A- benzoxazine, J = 11.0 and 1.2 Hz); 4.02 dd (1H, C ² H _B- benzoxazine, J = 11.0 and 2.7 Hz); 3.86 s (3H, OCH ₃ ); 1.47 d (3H, CH ₃ -aproxen, J = 6.8 Hz); 0.70 d (3H, CH ₃ -benzoxazine, J = 6.8 Hz).

¹⁹ F NMR (DMSO-d ₆ ) δ, ppm: 20.6 m (F ⁸ ); 1.75 ddd (F ⁷ , J = 20.8; 8.2 and 2.4 Hz).

Elemental analysis for C ₂₃ H ₂₁ F ₂ NO ₃ .

Calculated,%: C 69.54; H 5.33; N 3.52; F 9.56.

Found,%: C 69.70; H 5.33; N, 3.53; F 9.54.

GLC (Shimadzu GC-2010 chromatograph with flame ionization detector (ZB-5 quartz capillary column 30 m × 0.25 mm × 0.25 μm, carrier gas flow rate (nitrogen) 30 ml / min, flow rate through the column 1.0 ml / min) : basic substance content 99.9% (retention time of (S, S) -amide III 34.5 min).

Preparation of (S) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine ((S) -1).

80 g (0.21 mol) of compound III (D.I. 99.9%) are dissolved in 500 ml of glacial acetic acid, 500 ml of concentrated hydrochloric acid are added to the resulting solution, then heated at a temperature of 92 ° C for 10 hours. Then the reaction mass is evaporated in vacuo to a volume of 500 ml and poured into 4000 ml of distilled water. The precipitate formed is filtered off and washed on the filter 2 times with 100 ml of water. The filtrate and washings are neutralized with sodium carbonate to a pH of 8-9. The extracted oil is extracted with benzene (3 times 300 ml). The organic layer was washed with saturated NaCl (300 ml) and dried over anhydrous magnesium sulfate. After evaporating the solvent and drying in vacuo, 32.4 g (87%) of compound (S) -1 are obtained in the form of colorless fusible crystals with an enantiomeric excess (e.i.) 99.95% (HPLC: Knauer SmartLine chromatograph, Chiralcel OD column H, eluent hexane-isopropanol 40: 1; retention time τ _S 14-15 min; (R) -isomer τ _R 11-12 min).

Melting point from 28 to 29 ° C.

[α] _D from -7.3 to -7.7 (C2; chloroform).

¹ H NMR (400 MHz, CDCl ₃ ) δ, ppm: 6.55 ddd (1H, C ⁶ H, J = 10.0; 9.0 and 8.0 Hz); 6.27 ddd (1H, C ⁵ H, J = 9.0; 4.6 and 2.3 Hz); 4.28 dd (1H, C ² H _A , J = 10.5 and 2.7 Hz); 3.79 dd (1H, C ² H _B , J = 10.5 and 8.1 Hz); 3.51 dkvd (1H, C ³ HJ = 8.1; 6.5 and 2.7 Hz); 1.20 d (3H, Me, J-6.5 Hz).

¹⁹ F NMR (CDCl ₃ ) δ, ppm: 11.9 ddd (F ⁷ , J = 21.0; 10.0 and 4.6 Hz); 0.92 ddd (F ⁷ , J = 21.0; 8.1 and 2.3 Hz).

Elemental analysis for C ₉ H ₉ F ₂ NO.

Calculated,%: C 58.38; H 4.90; N, 7.57; F 20.52.

Found,%: C 58.45; H 4.78; N, 7.72; F 20.30.

GLC (Shimadzu GC-2010 chromatograph with flame ionization detector (ZB-5 quartz capillary column 30 m × 0.25 mm × 0.25 μm, carrier gas flow rate (nitrogen) 30 ml / min, flow rate through the column 1.0 ml / min) : basic substance content 99.9% (retention time of (S) -benzoxazine (S) -1 18.3 min).

Example 2:

Preparation of N - [(2S) -2- (6-methoxynaphth-2-yl) propionyl] -7,8-difluoro-2.3-dihydro-3 (S) -methyl-4H- [1,4] benzoxazine (III) .

To a solution of 30.0 g (0.162 mol) of (R) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine in 410 ml of toluene with stirring at a temperature of minus 40 ° С a solution of 20.1 g (0.081 mol) of compound II in 400 ml of dichloromethane is added dropwise. The reaction mass is stirred for 6 hours at minus 40 ° C, then heated to 0 ° C, washed with water (3 times 150 ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvent and drying in vacuo, the obtained residue was stirred in 500 ml of hexane at room temperature for 2 hours. The resulting suspension is cooled to minus 18 ° C and left at this temperature for 16 hours. The precipitate is filtered off in vacuo, washed on the filter 2 times with 50 ml of chilled hexane. After drying in air at room temperature, 23.2 g (72%) of compound III are obtained with a diastereoisomeric excess (qi) of 99.1% (HPLC: Agilent 1100 chromatograph, Phenomenex Luna C 18 (2) column 250 × 4.6 mm ; mobile phase acetonitrile: water 70:30; flow rate 0.8 ml / min; detection at 230 nm; retention times of (S, S) and (R, S) amides: 14.5-15.7 and 17.7-19.3 min). The resulting compound was recrystallized from 220 ml of ethanol to give 23.1 g (72%) of compound III as colorless crystals with a diastereoisomeric excess (qi) of 99.9%.

Preparation of (S) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine ((S) -1).

80 g (0.21 mol) of compound III (D.I. 99.9%) are dissolved in 500 ml of glacial acetic acid, 500 ml of concentrated hydrochloric acid are added to the resulting solution, then heated at a temperature of 96 ° C for 9 hours. Then the reaction mass is evaporated in vacuo to a volume of 500 ml and poured into 4000 ml of distilled water. The precipitate formed is filtered off and washed on the filter 2 times with 100 ml of water. The filtrate and washings are neutralized with sodium carbonate to a pH of 8-9. The extracted oil is extracted with benzene (3 times 300 ml). The organic layer was washed with saturated NaCl (300 ml) and dried over anhydrous magnesium sulfate. After evaporating the solvent and drying in vacuo, 31.7 g (85%) of (S) -1 are obtained as colorless fusible crystals with an enantiomeric excess (ee) of 99.95% (HPLC: Knauer SmartLine chromatograph, Chiralcel OD H column , eluent hexane-isopropanol 40: 1; retention time τ _S 14-15 min; (R) -isomer τ _R 11-12 min).

Example 3:

Preparation of N - [(2S) -2- (6-methoxynaphth-2-yl) propionyl] -7,8-difluoro-2.3-dihydro-3 (S) -methyl-4H- [1,4] benzoxazine (III) .

To a solution of 400 g (2.16 mol) of (R, S) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine in 4200 ml of dichloromethane with stirring and a temperature of minus 20 ° C. a solution of 268.6 g (1.08 mol) of compound II in 3000 ml of dichloromethane is added dropwise. The reaction mass is stirred for 6 hours at minus 20 ° C, heated to 0 ° C, then washed with water (3 times 2000 ml) and dried over anhydrous magnesium sulfate. After evaporation of the solvent and drying in vacuo, the obtained residue was stirred in 7200 ml of hexane at room temperature for 2 hours. The resulting suspension is cooled to minus 18 ° C and left at this temperature for 16 hours. The precipitate is filtered off in vacuo, washed on the filter 2 times with 200 ml of chilled hexane. After drying in air at room temperature, 334 g (78%) of compound III are obtained with a diastereoisomeric excess (qi) of 99.2% (HPLC: Phenomenex Luna C 18 (2) 250 × 4.6 mm; mobile phase acetonitrile: water 70 : 30; flow rate 0.8 ml / min; detection at 230 nm; retention times of (S, S) and (R, S) amides: 14.5-15.7 and 17.7-19.3 min). The resulting compound was recrystallized from 3000 ml of ethanol to give 330 g (77%) of compound III as colorless crystals with a diastereoisomeric excess (di.) Of 99.9%.

Preparation of (S) -7,8-difluoro-2.3-dihydro-3-methyl-4H- [1,4] benzoxazine ((S) -1).

80 g (0.21 mol) of compound III (D.I. 99.9%) are dissolved in 500 ml of glacial acetic acid, 500 ml of concentrated hydrochloric acid are added to the resulting solution, then heated at a temperature of 92 ° C for 10 hours. Then the reaction mass is evaporated in vacuo to a volume of 500 ml and poured into 4000 ml of distilled water. The precipitate formed is filtered off and washed on the filter 2 times with 100 ml of water. The filtrate and washings are neutralized with sodium carbonate to a pH of 8-9. The extracted oil is extracted with benzene (3 times 300 ml). The organic layer was washed with saturated NaCl (300 ml) and dried over anhydrous magnesium sulfate. After evaporating the solvent and drying in vacuo, 32.4 g (87%) of (S) -1 are obtained as colorless fusible crystals with an enantiomeric excess (e.i.) 99.95% (HPLC: Knauer SmartLine chromatograph, Chiralcel OD H column , eluent hexane-isopropanol 40: 1; retention time τ _S 14-15 min; (R) -isomer τ _R 11-12 min).

Claims (1)

The method of obtaining (S) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine of the formula (S) -1

the interaction of racemic 7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine of the formula (I)

with (S) -naproxen chloride of formula (II)

in an organic solvent medium, subsequent processing of the resulting mixture of amides of the formulas (III) and (IV)

,
hexane and hydrolysis of the isolated compound (III) with a mixture of acetic and hydrochloric acids when heated, characterized in that toluene or dichloromethane is used as an organic solvent, the reaction is carried out at a temperature of 0 - (- 40) ° С at a molar ratio of compound (I) - compound (II) = 1: 0.5, and after treatment with hexane, the precipitate is additionally recrystallized from ethanol, then the isolated compound of formula (III) is hydrolyzed at a temperature of 92-96 ° C for 9-10 hours.