MX2008006353A - Process for the preparation of delmopinol and derivatives thereof - Google Patents

Abstract

A process for the preparation of delmopinol (3-(4-propylheptyl)-4-morpholinethanol) or a derivative or a pharmaceutically acceptable salt, or a solvate thereof, including an hydrate, comprises reacting oxazolidin [2, 3-c]morpholine and a grignard reagent, and optionally converting the delmopinol (or derivative) free base into a pharmaceutically acceptable salt. The oxazolidin [2, 3-c]morpholine and the grignard reagent are useful as intermediates in the production process.

Description

PROCESS FOR THE PREPARATION OF DELMOPINOL AND DERIVATIVES THEREOF Field 3 to Invention The present invention relates to a process for the production of delmopinol or a derivative thereof, as well as to intermediates useful in the production process.

Background of the invention p delmop nol is the Non-Patented Name International (1NN) 3- (4-propylheptyl) - / 1-morpholine netanol (C? S No. / 98M- / 6-3). The salt of delmopinol hydrochloride (C? S No. 98092-92-3) is proposed to be used in the treatment of gingivitis, the structure of delmopinol hydrochloride corresponds to the formula: Di Terente processes for the production of delmopinol and its salts are known in the art. The document FP-A-038785 described several steps to produce this compound. In particular, the document I -? - 038/85 disclosed the preparation of demopinol by means of the alkylation of a 3-substituted sulphide, measured on the day of a primary amine with a bis (aloet i). et replaced by a disul LonaLo de dicti lengj icol suituto do, med i an te la reduction of a dicetomorpholine or by transforming the N-sus 11 morfolone in a group h i d roxi et i 1 o. EP-A-0426826 discloses a process for the production of the opinol comprising a loading of a morpholine oxide to obtain a morph 1 i n-i so-oxa / o 1 i dina, an opening of reducing ring, followed by the transformation of functional groups present in the side chain] and finally the alkylation of nitrogen to produce the op no]. The processes known to produce jmopinol are long and require the use of some very toxic reagents, which make their industrial exploitation difficult and expensive. Therefore, the provision of a new process for producing delmopinol is highly desirable. Brief Description of the Invention The present invention is based on the surprising realization that delmopinol and derivatives thereof, can be obtained by a short and convergent synthesis that takes place through a reaction between an oxazole compound i di n [2 , 3-CJ morpholin and a Grignard compound. According to a first aspect of the present invention, a process for the production of a compound of the formula (I) wherein Ri is an alkyl or aryl, or a pharmaceutically acceptable salt, or a sol vaLo thereof, which includes a hydrate, ( comprises reacting a compound of the formula (1 L) with a gpgnard compound of the formula (III) wherein X is a halogen selected from C 1, Br e 1 and Ri is an alkyl or a ryl portion, and optionally compound of the free base formula (L) obtained in a pharmaceutically acceptable salt. (ll) (III) the inventors have also found an efficient production process of the new oxa / olidin [2, 3-c] morpholm (11), starting from di-ethanol as it is available when it is available. with high yields and purity. Therefore, a second aspect of the present invention is the provision of a process for the production of oxazole i di n [2, 3-c] morpholma, which involves the reaction of ethanol amine with an alkyl haloacetate of (C? ~ C) to produce the 4 - (2-hi drox? _et? 1) -morfol? N-3-one known, followed by a reduction reaction, to produce oxa / ol idin [2, 3- c] Iro na. Both Stages can also be joined in a reaction in a container, which prevents isolation of 4- (2-hydroxyl) -mor folin-3-one.

(IHA) According to a third aspect of the present invention, the production of a specific gpgnard compound (TITA) is carried out by the treatment of a l-halo-4-propyl heptane with magnesium. According to a fourth aspect of the present invention, compounds (11) and (11 I?) Are provided. They are useful as intermediates for the production of a compound of the formula (LA).

(IA) According to a fifth aspect of the invention, the compounds (11) and (III) are used in the manufacture of a compound of the Tormula (1). The process of the present invention is an easy and efficient alternative for manufacturing delmopmol, delmopmol derivatives and / or pharmaceutically acceptable salts thereof, on an industrial scale. The process It is advantageous because it is a short and convergent synthesis, it avoids the use of toxic and flammable reagents, it uses mild reaction conditions and the delmopinol is obtained with high yields and at high purity. Peta Sense! Lacticity of the 1st Nomination A compound of the formula (I) is produced according to the present invention.

In the compound of the formula (I), i is an alkyl or aryl moiety. I, to the extent that I or I can be of any length, can be straight or branched chain and can be replaced, that is, I can contain atoms other than carbon in the main carbon chain. As used herein, the terms "alkyl" and "ar i lo" are given their usual meanings in the trécn? _ca. Preferably, the alkyl or aplo portion comprises between 1 and 30 carbon atoms, more preferably in the re? and 20 carbon loins, for example 6, 7, 8, 9 or 10 carbon atoms. The compounds of the formula (L) have been prepared where the R group is a 1-Propyl group, Benzyl Lo, 1-Ocphol, 1 -Lelpyl, 1- (2-et, 1) hex ? or 1 - (2-prop? 1) hexy 1 o. The preparation of these compounds are described in Examples 6 to 11. A preferred compound of formula (I) is delmopmol, which is represented below as formula (IA). In delmopinol, Ri is a chain of 4-propyl heptide.

(IA) According to the present invention, a compound of the formula (I) is obtained by a reaction between the oxazoli di n [2, 3-c] morfo 1 ina (II) and the compound Grignard (III) where X is a halogen selected from Cl, Br el, and Ri is an alkyl or aplo moiety as defined above and much more preferably a solid chain of a preferred compound of the formula (III), where R ± is a chain of 4-prop i 1 hept i lo is represented as the formula (111 A) below.

(IHA) Most preferably, the compound of the formula (TI I ") is 4-propylhexylmagnesium bromide .. As used herein, the term" Gpgnard Compound "is to be given its standard meaning, which is well known in the technique, is to say an organo-magnesium compound. For the prevention of doubt, a compound of formula (1) is prepared by reacting a compound of the formula (IL) with a compound Gr gn rd of the formula (III). A preferred embodiment of this general reaction comprises the production of delmopinol (formula (1 II?) By reacting a compound of the formula (TI) with the preferred Gpgnard compound of the formula (UTA) The formation of the Griqnard compound (I TI) ) and its subsequent reaction with the oxa / ol idine (II) is carried out in a suitable solvent such as ethers (C4-C12) and mixtures of the ethers with hydrocarbons at the (C5-C8) or aromatic (C6-C8) • Preferably the solvent is selected from the group consisting of d ether, tetrahydrofuran, methyl tetrahydroquinone, dabutylether, and the following mixtures: futrate-toluene tetrahydrofuran, tetrahydrofuran-xylene, meth I tetheto furafurano-toothene, methyltetrahydrofuran-xylene, dibutyl ether, xylene, dibutylether-toluene A compound of the formula (1), for example delmopino !, obtained by the process of the present invention can be converted into a pharmaceutically salt Accept, preferably in the hydrochloride salt and salts of delmopmol can be converted to Moxyl, by known methods described in the art. As a way of For example, demopinol hydrochloride can be prepared from delmopinol by reaction with hydrochloric acid in any suitable solvent. Examples of suitable solvents are, for example, toluene, xylene, mel ili isobutyl ketone, dibutylether, methyl ether, butyl ether, ethyl acetate and mixtures of the same. I J composed of the formula (Ll) can be obtained by means of the process summarized in i sque a 1, which can be carried out in two stages or as a reaction in a container. As used in this, the term "a reaction in a container" is to be given its normal meaning in the art, ie the compound of formula (II) is produced in an individual reaction reagent, such that at least a proportion of the compounds (V) and (VI) are converted to the compound (IV) and subsequently the compound (LL), without the isolation of intermediates. The alternative to a reaction in a vessel is a two-step reaction wherein the formula (IV) is produced in a first stage and the second step of converting (IV) to UF) is carried out separately. rSOUl MA 1: (V) (VI) (IV) (II) In the formula (VI), X is a halogen selected from Cl, Br e J, and Ri is an alkyl radical of (C 1 -C 4). Preferably, the compound of the formula (VI) is methyl chloroacetate. The reaction between d 1 ethane 1 a 1 na (V) and the haloacetate of the formula (VI) is preferably carried out in the presence of a suitable base and a suitable solvent. Examples of suitable bases are sodium hydride, sodium methoxide, Ler-bul potassium oxide and sodium fer-butoxy. The best results are obtained with fer-butóxa do de potasio. Suitable solvents are for example tetrahydrofuran, xylene, toluene or dibutyl ether. The reaction between the di-ethanol amine (V) and the halodolyl (VI) can be carried out at a temperature between room temperature and the reflux temperature of the solvent used. Preferably, the reaction is carried out at high temperatures (ie slightly less than the reflux temperature of the solvent, for example 50% of the reflux temperature or above, preferably 60%, 70%, 80% or 90% of the reflux temperature) to avoid the thickness of the crude mixture by insolubility of di ethane 1-NaOH to low temperatures. The compound (TV) can be isolated from the reaction medium with high performance as an oil, which can be used without purification in the next step. If required, it can be purified by d is 111 aci on. 3-mor fol i nona (IV) can also be prepared by a process described in the literature (Aust rallan Journal of Chemistry, 1996, volume 49, pages 1235-1242). However, this process uses an excess of Lactic acid reagent, goes through an unstable intermediate and proceeds with low yields. The reduction of 3-morphine and none (IV) to produce the oxa / ol idine (I I) is carried out by a reducing agent. I examples of reducing agents are hydride of bis (/ -methox and ox i) to 1 um of sodium (V ilri of), sodium bo rrome, Li rdruro Lithium aLupunio ehid ru of bi set ox ia Sodium Luminio. A preferred reducing agent is b hids (2-methoxyethoxy) hydride at 1% sodium. The reduction reaction is carried out in a selected solvent of an aromatic hydrocarbon of (Ce-Cs) such as toluene or xylene and an ether of (C4-C? 2) such as diethylether, fumed tet rah id ro, dibutylether , methyl-tertiary butylether and diethylene glycol di-vinyl ether. Preferably, when the process for producing the compound of formula 11 is carried out in a vessel, the alcohols generated during the reaction between the di ethanolamine and the compound of the formula (VI) are distilled before adding the reducing agent. fL composed of the formula (111) can be produced by reacting an alkyl halide or ap lo with magnesium. Preferably, the halide is in the terminal or secondary position. In a preferred embodiment, as illustrated in Scheme 11, the compound of the formula (IIIA) is previously prepared by treating a compound of the formula (VII) wherein X is a halogen selected from C 1, Br and I, with magnesium. Any suitable solvent for Grignard reactions such as (C4-C12) ethers and mixtures of such ethers with (C5-C8) aliphatic hydrocarbons or (CT-CS) aromatics can be used for the formation of the Gpgnard compound. The Gpgnard compound of the formula (III) is not isolated and used in solution. Its formation is easily affected by the disappearance of magnesium and the brownish coloration of the solution. SCHEME L I: (V) (MIA) CJ composed of the formula (VII) can be prepared from the corresponding hydroxyl compound of the formula (VIII) by a reaction of hal ogenac 1 on.

(VIII) Preferably, in the compound of the formula (VII), X is bromine and is preferably obtained by a bromination reaction of the compound (VL11) with aqueous hydrobromic acid. The compound of the formula (VT I I) can be prepared by the process described in Justus Liebigs AnnaJen Chemie, 1966, volume 693, page 90, the content of which is incorporated herein by reference. Throughout the description and the claims, the word "comprises" and variations of the word, such as "comprising", are not proposed to exclude other technical aspects, additives, components or steps. The objects, advantages and additional features of the invention will be apparent to those skilled in the art in the description of the invention or can be learned by the practice of the invention. The following example lenses are provided by way of illustration and are not intended to be limiting of the present invention. EXAMPLES Example 1: Production of 4- (2-hydroxyl) morphol i-3-one (IV) Potassium tert-butoxide (176 g, 1.1 eq.) Was added to 1440 ml of toluene. The suspension is slow at 75 ° C and it was maintained for 30 minutes until the white solid solution was com- posed. At this temperature, diethanolamine was added slowly (150 g, 1 eq.). The thick pale yellow suspension was maintained with vigorous stirring for 30 minutes and methyl chloroacetate (163 g, 1.05 eq.) Was slowly added. The solution was maintained at the same temperature for two hours. Methane was added to the heated mixture! (600 ml) and cooled to room temperature, the salts were filtered and the organic layer was concentrated to dryness. Compound (IV) was obtained as an orange oil (204 g, 98%) which was distilled under high vacuum to obtain it as a highly pure colorless oil (80%, bp5 J80 ° C). LR (film) (n cm-1): 3410, 2934, 2874, J633, J501, J350, J1 J. MS (El), (m / z,%): J45 (Mi., 1 2), 114 ( M-CH20H, 100), 86 (M-NC2H40H, 65), 74 (M- / 1, 7), 56 (M-89, 41), 42 (M-J03, 44). Example 2: Production of oxa zol idm f 2, 3-c | mor fo l? _na (T T) To a solution of 3-mor fo 1 i none (IV) (20 μg, J eq.) In toluene (1450 ml), Vitride solution (412 g, 2 eq., 70% in toluene) was slowly added at room temperature. ambient. The reaction was maintained for 15 min at this temperature. Aqueous sodium hydroxide solution was added slowly to the 50% (360 g, 3.15 eq.) Keeping the mixture at room temperature. The mixture was heated to 50-60 ° C and the aqueous layer was separated and extracted at the same temperature with toluene (924 ml). Both organic layers were concentrated together until dry. The oxazole Ldina (II) (154.5 g, 84%) was obtained as a brownish-brown oil, which was destined to give a highly pure colorless oil (65 g, bp, 80 ° C). IR (film), (n cm-1): 2865, J676, 1457, 1297, 1113, J046. MS (El), (m / z,%): 129 (Mt., 50), 99 (M-CII20, 100), 98 (M-CH30, 90), 84 (M-C2H50, 10), 71 ( M-C3II60, 51), 56 (M-73, 37), 42 (M-87, 47), 41 (M-88, 65). EXAMPLE 3: Production of oxazo 1 idin | 2, 3-c | mor fo I i na (LL) in a reaction in a vessel starting from the end of the year Potassium tert-butoxide was added (1/6) g, Jl eq.) to 1440 ml of toluene. The suspension was heated to 75 ° C and maintained for 30 min. until the dissolution of the white solid is complete. At this temperature, amine ethanol (150 g, 1 eq.) Was slowly added. The thick pale yellow suspension was maintained with vigorous stirring for 30 min. and methlo-loxazoacetate (163 g, 1.05 eq.) was slowly added. The solution was maintained at the same temperature for two hours. The reaction mixture was cooled to 30 ° C and the VLtride solution (412 g, 2 eq., 70% in toluene) was slowly added at room temperature. The reaction was maintained for 30 min at this temperature. Solution was added slowly 50% aqueous sodium hydroxide (360 g, 3.15 eq.) keeping the mixture at room temperature. The mixture was set at 50 ° C and the aqueous layer was separated and extracted at the same temperature with toluene (924 mJ). Both organic layers were concentrated together until dry. Oxazolidm (L) (J47 g, 80%) was obtained as a brownish-brown oil. E empl o 4_j Produce i ón __ dc_ 4 - (2_-h? _ D ro_x i e 111) -3- (4 -prop i lhept i 1) mor f o 1 i na (1A) To a suspension of J.3 g of magnesium (1 eq.) In 24 ml of toluene and J8 mJ of tetrahydrofuran was added a small amount of iodine. The mixture was heated to 64 ° C and 12 g of 1-bromo-4-prop? 1 heptane (VII) (1 eq.) Was added slowly controlling the ex- tensiveness of the reaction. The mixture was kept at the same temperature for 2 hours and cooled to room temperature, obtaining a solution of the compound (III). A solution of 7 g of oxazoJidma (II) (1 eq.) In 7 mJ of toluene was added to the previously prepared Grignard compound (11 L) at room temperature in 30 mm. 50 mJ of toluene and 50 ml of aqueous ammonium chloride solution were added and the resulting mixture was stirred at 40 ° C until the dissolution of the salts was complete, obtaining a biphasic mixture. J_, the organic layer was separated at 40 ° C. The aqueous layer was extracted with 50 mJ of toluene at 40 ° C. The organic layers were concentrated together to dryness, obtaining 8.8 g of 4- (2-hydroxy et i J) -3- (4-prop? 1 hepti J) mor folin as an orange oil. LR (peJIcuJa), (n cm-J): 3446, 2951, 2925, 2859, 1628, 1458, JJ28, 1048. MS (CL), (m / z,%): 271 (Mi., J), 270 (M-II, J), 240 (M-CI120I1, 46), 130 (M-141, 100), 100 (M-171, 29). Example 5: Production of 4- (2-hydroxyl l) -3- (4-propjJhept? 1) hydrochloride To a solution of 7.4 g of 4 - (2-hydroxyethyl) -3- (4-propyl-1-heptyl) morphine in 22 ml of methyl isobutyl ketone at room temperature was added hydrochloric acid. concentrate (2.7g, J eq.). The solution was concentrated to dry at 60 ° C. The oil was redissolved in 21 ml of methyl iso-butyl ketone, the solution was seeded and stirred for 2 hours at 0 ° C. The white solid was filtered, washed with 20 ml of cold methyl iso-butyl ketone and dried to obtain 5.9 g of 4- (2-hydroxyl) -3- (4-propheptyl) hydrochloride. morpholine (delmopmol hydrochloride). 1 H-NMR (CDCJ 3, 400 MHz), (d ppm): 0.88 (611, m, HJ5), 1.2-1.4 (13H, m), 1.8-2.0 (2H, m), 2.8-3.4 (5H, m), 3.4-4.4 (6H, m). 13 C NMR (CDC13, 400 MHz), (d ppm): 14.26 (C15), 19.47, 19.52 (C14), 22.87 (CIO), 27.11 (C9), 33.25 (CU), 35.54, 35.62 (C13), 36.59 (C12), 49.25 (C5), 53.20 (C7), 55.93 (C3), 57. 08, 59.89 (C8), 63.1, 63.2, 65.0 (C6), 67.7 (C2). Example 6: Synthesis of 4- (2-Hydr xi_e t_i 1) -_3_-p ropymorpholine (IB) B 43 g of oxazolidine (II) was dissolved in 215 ml of THF. At room temperature, a solution of 20% n-Propylmagnesium chloride in THF (172 g, 1 eq) was slowly added. The mixture was stirred for 15 minutes. The mixture was concentrated to dryness under vacuum and 100 ml of Toluene and 64 g of saturated aqueous ammonium chloride solution were added and the resulting mixture was stirred at room temperature until the dissolution of the salts obtaining a biphasic mixture was complete. The organic layer was separated and the aqueous layer was extracted with 265 ml of Toluene at room temperature. The organic layers were concentrated together until dry, obtaining 33.4? 4 - (2-1-1: id roxyethyl) -3-propylmorpholine similar to an orange oil, which was further purified by column chromatography on silica gel eluting with a mixture of CH2C12 / MeOH / NH3 (99/1 /1), obtaining the aforesaid product as a colorless oil. 1 H-NMR (CDC13, 300 MHz), (d ppm): 0.92 (3H, t, J = 7.2 Hz, Hll), 1.36 (4H, m, I19 / H10), 2.36 (3H, m, H3 / H7) , 2.82 (1H, ddd, JJ = J2.3, J2 = 4.9, J3 = 3.0 Hz, 115), 2.94 (111, ddd, JJ = 12.3, J2 = 7.8, J3 = 4.8 Hz, 115), 3.44 (JH , dd, JJ = 1J.2, J2 = 6.9 Hz, H2), 3.88 (1H, dd, J1 = 1J.2, J2 = 4.9 11 /, 112), 3.62 (JH, dd, Jl = 4.8, J2 = 7.8 Hz, 116), 3.67 (111, dd, JJ /.8, J2-4.9 Hz, 116), 3. / 5 (211, m, 118). J 3C-NMR (CDC13, / 5 Mil /), (d ppm): 14.3 (CU), J9.3 (CJO), 29.2 (C9), 49.9 (C5), 54.6 (C7), 57.7 (C8), 59.5 (C3), 66.9 (C6), /O.4 (¿). IR (film), (n cm-1): 3444, 2958, 2863, 1456, 1366, JJ29, 1052. MS (FL), (m / z,%): 1/3 (Mi., 42), 142 (M-CH20H, JOO), 130 (M-C3H7, 100), 112 (M-C3H7-H20, 14), 100 (M-3, 8), 84 (10), 71 (5), 56 (20 ), 42 (14). IjempJo 7 of 4- (2-111 drox i eti 1) -3- (J -hept i 1) mor fo I i na (IC) 200 g of 1-bromoheptane at 65 ° C were added slowly to a suspension of 32.6 g of magnesium, 0.5 g of iodine and 2.4 mJ of Dibromoethane in a mixture of J 82 ml of THF and 400 ml of toluene. The reaction mixture was stirred at the same temperature for 3 h. When the formation of the corresponding Grignard compound was complete, the solution was cooled down to room temperature and a solution of J58 g of Oxazolidine (II) in 500 ml of toluene in J hour. The mixture was stirred for 30 m n. and then added to a solution of 795 mJ of 5% aqueous HCl aL. The organic layer is decanted and concentrated to dryness. The compound (IC) was obtained as an orange oil (J79 g). MS (El), (m / z,%): 229 (MI., 1), 198 (M-CH20H, 25), J30 (M-C7H15, JOO), 112 (M-C7H15-H20, 4), 100 (M-73, 30), 86 (5 56 (10), 4J (8)) Example 8 Synthesis of 4- (2-H? Drox? Et? L) -3-benzylmorphine (lD ) Following the same procedure described for (IC) and starting with 10 g of Benzyl chloride and 11 g of Oxazole idine (II), 7.9 g of the compound (JD) was obtained as a yellow oil cLaro. MS (EJ), (m / z,%): 22J (M-, 1), 190 (M-CH20I1, 5), 130 (M-C7I17, J00), 91 (CH2C6H5, 8). EXAMPLE 9 Symptoms of 4- (2-11 ídroxiet i 1) -3- (1-oct l) morfol? Na (JE) g of 1-Bromooctane were slowly added to a suspension of 3.5 g of magnesium and 7.5 mg of iodine in 41 ml of THF at 65 ° C. The reaction mixture was stirred to the same temperature for 2 h. When the corresponding Gpgnard compound was prepared, the mixture was cooled down to 5 ° C and a solution of 16.7 g of Oxa / ol idine (Ll) in 40 ml of toluene was added in 1 hour. The mixture was stirred at 5 ° C for 30 min. and the reaction was warmed to room temperature. The mixture was added to an aqueous solution of 5% HCl and stirred for 30 ml. The organic layer was decanted, dried and concentrated to dryness to obtain 19 g of the desired compound as a brown oil. MS (ET), (m / z,%): 243 (ML, 5), 242 (M-II, 5), 212 (M-CH20H, 50), 198 (M- (CH2) 20H, 8), J30 (M-C8HJ7, JOO), JJ2 (M-C8II 17-H20, 8), 100 (M- / 3, 30), 86 (8), / l (8), 56 (9), 4J (J4). Example JO: Synthesis of 4- (2-11 i d rox _? _ C_ 1 L) 3- (1- (2-eti lhexi 1) mor folí na (J F) Following the same procedure described for (IE) and starting with 25.5 g of l-Bromo-2-ethexano bromide and J6.2 g of Oxazole idine (N), J9.8 g of the compound (1 F) They obtained like a dark orange oil. MS (El), (m / z,%): 243 (MI., J), 2J4 (M-C2II5, 6), 2J2 (M-C1I20II, 11), 186 (M-C4H9, 4), 156 ( 8), J30 (M-C8H1 /, JOO), JOO (46). Example 11: Synthesis of 4- (2-111 d roxi c l) -3- (1- (2- prop lpenti 1) morfoJ i n (LG) Following the same procedure described for (IE) and starting with 5.8 g of 1-Bromo-2-prop i Ipent no and 4 g of OxazoJidine (11), 3.3 g of the compund (11) were obtained as an ace ile mari l the dark. MS (11), (m //,%): 243 (Mi., 1), 212 (M-CI120H, 8), 200 (M-C31I7, 6), 1/0 (10), J 30 ( M-C8H17, 100), JOO (50).

Claims (18)

1. ?? CLAIMS 1. A process for the production of a compound of the formula (I), wherein Ri is an alkyl or aryl portion, or a pharmaceutically acceptable salt, or a solvate thereof, which includes a hydrate, characterized in that it comprises reacting a compound of the formula (11) with a Gpgnard compound of the formula (ILL) wherein X is a halogen selected from C 1, Br and I and Ri is an alkyl or a ryl portion; and optionally converting the free base of the compound of the formula (T) obtained into a pharmaceutically acceptable salt. (ll) (III)
2. 2. The process according to claim J, characterized in that in formula I (l I l) X is bromine.
3. 3. The process according to claim J or claim 2, characterized in that the formula J L 1) is the formu la (1 L I A)
4. 4. The process in accordance with the claim 3, characterized in that the compound of the formula (1) that is produced is of the formula (1A). (IA)
5. 5. The process according to any preceding claim, characterized in that the reaction is carried out in a solvent selected from the group consisting of: (C4-C2) ethers and mixtures of such ethers with hydrocarbons aJifatLcos of (C5-) C8) or aromatics of (Cß-Cß), or combinations thereof.
6. 6. The process according to any preceding claim, characterized in that the compound of the formula (J1) is obtained by a reduction reaction of a compound of the formula (IV). (IV)
7. 7. FJ process in accordance with the claim 6, characterized in that the reduction reaction is carried out with a reducing agent selected from bis (2-methoxyethoxy) hydride at umin or sodium, sodium borohydride, lithium aluminum hydride and hydride from bi sel oxi al umi sodium child.
8. 8. EJ process in accordance with the claim 7, characterized in that the reducing agent is sodium bis (2-methoxethoxy?) Aluminum hydride.
9. 9. The process according to which of the claims 6-8, characterized in that the reduction reaction is carried out in a solvent selected from an aromatic hydrocarbon of (Cß-Cs) and an elcr of (C4-C? 2) .
10. 10. The process according to any of claims 6-9, characterized in that the compound of the formula (IV) is obtained by the diethanolamine reaction of the formula (V) with a compound of the formula (VI) wherein X is a Lalogen selected from Cl, Br and I, and Rl is an alkyl radical of (CJ-C4), in the presence of a base. (V) (VI)
11. 11. EJ process in accordance with the claim JO, characterized because the base is selected from sodium hydride, sodium methoxide, potassium tert-butoxide and ter- sodium butoxide.
12. 12. The process according to any of claims 10-11, characterized in that the compound of the formula (VI) is methyl chloroacetate.
13. 13. The process for producing a compound of the formula (I I) according to any of claims 6-12, falls into step because it is carried out in an individual reaction vessel.
14. The process according to any of claims 3-13, characterized in that the Gpgnard compound of the formula (111?) Is previously prepared by reacting a compound of the formula (VII) wherein X is a halogen selected from the group that with I of Cl, Br and I, with magnesium. (VI!)
15. 15. A compound of the formula (TJ (ii)
16. 16. A compound of the formula (1J1A), characterized in that X is a halogen selected from CL, Br e J. (IIIA)
17. 17. EJ compound in accordance with the LO reivmdicac? 16, characterized in that X is bromine.
18. 18. Use of a compound according to any of claims J5 to I I, characterized in that it is for the manufacture of dolmopinol