CZ299699B6 - Method of preparing [ 3S -( 3{alpha}, 4{alpha}{beta}, 8{alpha}{beta})]-3-N -tert -butyl -decahydro -3 ûisoquinolinecarboxamide with high optical yield - Google Patents

Abstract

The present invention relates to a continuous process for the preparation of [ 3S -( 3{alpha}, 4{alpha}{beta}, 8{alpha}{beta})]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide with a high optical yield comprising continuously reducing N-tert-butyl-1,2,3,4-tetrahydro-3(S) isoquinolinecarboxamide dissolved in an inorganic solvent to 3S- (3{alpha}, 4{alpha}{beta}, 8{alpha}{beta})]-N-tertbutyl-decahydro-3-isoquinolinecarboxamide with hydrogen in a fixed bed reactor charging a noble metal catalyst supported on an inorganic oxide carrier with the range of the metal content between 0.5 and 10 percent by weight, at a temperature in the range of about 80 and 170 degC, under the pressure in the range of about 2.07 to 17.2 MPa and at the Weight Hourly Space Velocity (WHSV) in the range of about 0.1 and 10 he-1, wherein the molecular ratio of hydrogen to N-tert-butyl-1,2,3,4-tetrahydro-3 (S)-isoquinolinecarboxamide is in the range of about 4 and 10, N-tert-butyl-1,2,3,4-tetrahydro-3 (S)-isoquinolinecarboxamide content in an organic solvent is in the range of about 2 and 50 percent by weight and the inorganic oxide carrier has the Brunauer Emmett Teller (BET) surface area in the range of about 10 and 1,000 me2/g, the median pore diameter of the major pores of less than 200A and the total pore volume in the range of about 0.2 and 1.2 cc/g.

Description

(57)

The present invention relates to a continuous process for the preparation of [3S (3a, 4ap, 8aP)] - N-tert-butyl-decahydro-3-isoquinolinecarboxamide from N-tert-butyl-1,2,3,4-tetrahydro, 3 (S) isoquinolinecarboxamide with high Optical yield of continuously reducing N-tert-butyll, 2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide with hydrogen in an organic solvent to [3S- (3a, 4aP, 8aP)] - N -tert-butyldecahydro-3-isoquinoline-carboxamide in a fixed bed reactor, which is charged with a noble metal catalyst on an inorganic oxide support with a metal content between 0.5 and 10% by weight, at a temperature in the range of 80 to 170 ° C, below at a pressure ranging from 2.07 to 17.2 MPa and at a mass hourly space velocity in the range of 0.1 to 10 h * ¹ , and wherein the molecular ratio of hydrogen to N-tert-butyl-1,2,3,4-tetrahydro3 ( S) -isoquinolinecarboxamide is in the range of 4 to 10, the content of N-tert-butyl-1,2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide in the organic solvent is in the range of 2 to 50% wt., and an inorganic oxide carrier has a surface area according Brunaueurera, Emmett and Keller in the range of 10 to 1000 m ² / g, a mean pore diameter of the pores is much smaller than 2/10 ^'8 and ni the total pore volume in the range 0.2 to 1.2 cm ³ / g.

CZ BO

Process for the preparation of [3S- (3a, 4a, 8a, 8a)] - N-N-N-butyl-decahydro-3-isoquinolinecarboxaniide in high optical yield

Technical field ...... - ........

The present invention relates to a continuous process for the preparation of [3S- (3α, 4α, β, 8α)] - N- tert -butyl-decahydro-3-isoquinolinecarboxamide by reducing N-tert-butyl-1,2,3,4-tetrahydro-3 (S) -isoquinoline carboxamide with a noble metal supported catalyst in a fixed bed reaction system.

BACKGROUND OF THE INVENTION [3S- (3a, 4a, 8a, 8a / 7)] - N- tert -butyl-decahydro-3-isoquinolinecarboxamide (hereinafter referred to as "DHIQ") is one of the key intermediates in synthesis of compounds useful as excitatory amino acid receptor antagonists for HIV protease inhibitor for the treatment of acquired immune deficiency syndrome (AIDS).

The procedure for the synthesis of N-tert-butyl-1,2,3,4-tetrahydro-3 (S) -isoquinoline carboxamide (hereinafter referred to as "TICC") by phosgenation by amination of the phenylalanine derivative is described in

US 5,587,481, David R. Allen et al. US 5,587,481 also discloses a process for producing DHQ by hydrogenating TICC using 5% (w / w) Rh / C or Rh / alumina catalysts in either aqueous or organic media at 100 ° C and 2.41 MPa. After the reaction, the solution must be filtered to remove the catalyst, followed by removal of the solvent and crystallization to yield

DHIQ. However, under these reaction conditions, the DHIQ yield is 62 to 67% based on TICC, due to the low chiroselectivity of the rhodium catalyst.

Hoffmann, European Application EP 0 432 695 A2, discloses the use of 5% (w / w) Rh / C catalyst to reduce tetrahydroisoquinoline-3-carboxylic acid to [3S- (4aS, 8aS)] 30 decahydroisoquinoline-3-carboxylic acid in acetic acid at 80 ° C and 14.2 MPa:

This reaction was carried out for 24 hours. Racemization occurred and the yield of the desired enantiomer was about 65%.

Sato et al., European Application EP 0 751 128 A1, describes a process for producing DHIQ from TICC reduction using Rh, Pt and Ru. In Example 3 of the synthesis, the TICC was reduced with 5% (w / w) Rh / C catalyst at 3.04 MPa and 100 ° C for 20 hours. After filtering off the catalyst and further processing, DHIQ yields of primary and secondary crystals were 52.1%, respectively. 20.7%.

In general, batch processes for preparing DHIQ from TICC consist of: (1) a powdered catalyst loaded into a batch reactor equipped with mixing and heating / cooling systems; 2) injecting the reactant in the solvent; 3) the reactor is sealed and purged with inert gas; 4) introducing pressurized hydrogen while heating the entire contents to the desired temperature; 5) shut off the hydrogen supply and continue the reaction until it is stopped by the pressure drop caused by the reduction of the reactant; 6) after cooling to room temperature, the product is removed in a solvent,

As will be appreciated by those skilled in the art, the disadvantages of the batch process mentioned above are: 1) the process is inherently non-productive and is complicated by the use of batch reactors; 2) it is difficult to control the reaction conditions, for example the hydrogen partial pressure, because the process is dynamic; 3) recovery and reuse of the catalyst after the reaction requires a series of procedures; 4) there is a risk of fire and explosion because a reduced catalyst is already used; 5) DHIQ yield is not good.

SUMMARY OF THE INVENTION The intensive and thorough development of the present inventors to solve the problems encountered in the prior art has led to the development of a new method, better in optical yields.

It is therefore an object of the present invention to provide a process for the production of optically active [3S- (3a, 4a _, 8a _, 8a)] -N-tert-butyl-decahydro-3-isoquinolinecarboxamide, an intermediate useful in the synthesis of compounds for the treatment of viral diseases N-tert-butyl-1,2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide with a noble metal supported catalyst in a fixed bed reaction system with high optical yield.

In accordance with an aspect of the invention, there is provided a process for the preparation of [3S- (3a, 4α, β, 8α)] - N - tert -butyl 20 decahydro-3-isoquinolinecarboxamide with N-Zcrc-biityl-1,2,3,4 -tetrahydro-3 (S) -isoquinolinecarboxamide with a high optical yield, consisting in the continuous reduction of N-tert-butyl-1,2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide with hydrogen in an organic solvent to [3S43a.4a (R, 8a)] - N - N -butyldecahydro-3-isoquinolinecarboxarnide in a fixed bed reactor, which is charged with a noble metal catalyst on an inorganic oxide support with a metal content range of 0, 5 and 10 wt.%, At a temperature in the range of 80 to 170 ° C, under a pressure in the range of 2.07 to 17.2 MPa, and at a mass hourly space velocity in the range of 0.1 to 10 h ^-1 , and wherein the molecular ratio of hydrogen to N- tert -butyl-1,2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide is in the range of 4 to 10, the content of N- tert -butyl-1,2,3,4-tetrahydro -3 (S) -isoquinolinecarboxamide in an organic solvent is in the range of 2 to 50% by weight, and the inorganic oxide carrier has a Brunaueurer, Emmett & Keller (BET surface area) surface area in the range of 10 to 1000 m ^{* 2} / g, median pore diameter for most pores. is lesser

2. i 0 * m and a total pore volume in the range 0.2 to 1.2 cm ³ / g.

The starting material in the present invention is the isoquinoline carboxamide, N-tert-butyl-1,2,3,4-tetra35 hydro-3 ($) - isoquinolinecarboxamide (TICC), which can be prepared by either a multi-step synthetic process involving phosphogenation and amidation of the designated phenylalanine derivative (Allen, DR, et al., US 5,587,481) or by any similar method (SatoT., et al., European Application EP 0 751 128 A1). To obtain DHIQ with high optical yield, TICC with the following specifications is preferred: 1) gas chromatographic purity not less than 99.2%; 2) the R (+) enantiomer by chiral HPLC of not more than 1%; 3) melting range 92-100 ° C.

_r ť rr «v-1. ^ ·

To achieve a higher spatial time yield, to reuse the catalyst repeatedly without post-treatment steps, and to reduce the number of processing steps, the reaction is carried out

In the fixed bed reactor of the present invention. There are no restrictions on the type of reactor and the flow direction of the reactant. However, to allow contact between the reactants, the reaction is preferably carried out in a scrubbed-bed reactor type with both hydrocarbon (s) and hydrogen overflow mode to facilitate contact between the reactants. The reactor must be equipped with suitable devices for uniform distribution of all reactants.

The reaction must be carried out in a solvent medium to easily inject TICC into the reactor and to easily remove reaction heat when the reduction is highly exothermic. Hydrocarbons which do not react with hydrogen and TICC and which can substantially release TICC can be used as solvents. The solvent used in the present invention is any type of single hydrocarbon or mixture thereof, such as acetic, propionic, lactic or isolactic acid, methanol, ethanol, n-propanol, isopropanol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, methyl acetate , ethyl acetate, n-propyl acetate, iso-propyl acetate, n-butyl acetate, n-hexane, iso-hexane, n-heptane, iso-heptane, n-octane or iso-octane. The concentration of TICC in the organic solution is 2 to 50% by weight. Preferably, the concentration is 5 to 30% by weight. Depending on the TICC concentration, the solvent may be heated to dissolve all the solid particles. During TICC dissolution, the TICC solution must not be injected into the reactor. Thus, two or more dissolution reactors can be prepared and alternatively operated to provide fully dissolved TICC to the reactor,

The TICC can be reduced to DHIQ using molecular hydrogen and a noble metal supported catalyst. Any inorganic oxide such as alumina, silica, silica-alumina, zirconium oxide, titanium oxide or molecular sieves is suitable as the carrier. Of these inorganic materials, alumina and silica are preferred. The support may have a BET surface area between

10 and 1000 m ² / g. Preferably, the BET of the support surfaces is between 20 to 500 m ³ / g and most preferably 50 to 500 m ³ / g

300m ² / g. The pore volume of the carrier is preferably 0.2 to ^1.2 cm ² / g, more preferably 0.3 to 1.0 cm ² / g. There are no restrictions on the pore size distribution supports but the preferred support is a mean value of the pore diameter for most pore Merisi than 2.10 ^-8 m, measured by adsorption / desorption of nitrogen. More preferably, the median pore diameter of the carrier is less than 1,5,10 ^-8 m. The shape of carrier particles may be circular, cylindrical, granular, or may have any other form to provide suitable mechanical properties, however, are preferred pellets of either circular or cylindrical type.

Pd, Pt, Ru, Os or a mixture thereof is suitable as a noble metal. Preferably, Ru or Os is used. The noble metal concentration (s) is preferably between 0.5 and 10 wt%, more preferably between 1 and 10 wt%

6 wt. When the metal content is less than 0.5 wt%, the activity and selectivity to DHIQ are low.

When the metal content is greater than 10% by weight, the cost of the metal makes the process uneconomical. The metal is applied to the support in any suitable manner, for example by initial moisture impregnation, impregnation with excess water, spraying, or mechanical agitation. After the metal is loaded, the catalyst is calcined in air or an inert gas atmosphere at a temperature between 300 and

7 00 ° C for more than two hours. Preferably, the calcination temperature is 350 to 600 ° C. When the temperature is below 300 ° C, calcination is incomplete and the precursor compound may not undergo decomposition. When the temperature is higher than 700 ° C, the metal dispersion is too low for any substantial catalytic activity. After loading the catalyst, the catalyst must be reduced by flowing hydrogen at a temperature between 50 and 400 ° C for at least one hour, depending on the metal used in the catalyst.

The reduction of TICC to DHIQ is performed at 2.07-17.2 MPa, 50-200 ° C, and a mass hourly space velocity (WHSV) of 0.1-10 h ^-1 . Preferably DHIQ is prepared at 3.45 to 13.8 MPa and WHSV of 0.2 to 6 h ^-1 . More preferably, the reaction is carried out at 5.52-11 MPa, 100-160 ° C and a WHSV of 0.5-4h ^-1 . When the reaction is carried out under conditions out of the above range, the yield is low and the catalyst is deactivated fairly quickly, and thus the advantage of continuous reduction disappears.

There is no limitation in the molecular ratio of hydrogen to TICC, except when it exceeds three to ensure 100% conversion of TICC. However, considering economics, this ratio is between 4 and 10. Hydrogen

In excess of stoichiometry, the reaction stoichiometry may be released and repressurized by a recycle compressor and recycled to the reactor.

The reaction products exiting the reactor are fed to a solvent recovery apparatus wherein at least a portion of the solvent is separated from the rest of the product. The device may be of any type, such as a distillation tower or a fast evaporator. The DHIQ bottom product, or concentrate, is fed to the crystallizer. During crystallization, a hydrocarbon solvent such as hexane or heptane is used.

Overview of the figure in the drawing

Giant. 1 is a graph illustrating the relationship between yield and time in a stream using the process and catalyst of the invention

DETAILED DESCRIPTION OF THE INVENTION

The following examples describe the invention in detail for the purpose of explanation.

and

Preparation Example 1

Preparation of catalysts

6.35 g of ruthenium chloride (Aldrich, RuCl ₃ ) was dissolved with 40 ml of redistilled water in a 100 ml measuring cup. For 100 g of Norton SA 3177 alumina (surface area 100 m ² / g; pore volume 0.49 cm ³ / g, mean pore diameter 1.10 ⁸ m) that was in a small cup connected to a variable speed motor, was evenly sprayed The solution containing Ru was rotated at 50 revolutions / min. After metal deposition, the catalyst was calcined in a muffle furnace at 550 ° C for 6 hours. X-ray fluorescence analysis showed a Ru content of 3.0 wt%.

Preparation Examples 2-4 Catalyst Preparation

All procedures were similar to Preparation Example 1 except using 100 g of different. carrier materials (Table I)

Table I

Prep. .example no. Carrier Surface area Volume, pore median diameter, pore cm 7g 10 ¹⁰ m m7g Prep :. .example 2 alumina Norton 6173 220 0.62: 70 Prep. Example 3 alumina Norton 6173 '255 1.14 70/5000 · Prep: Example 4 oxide. Silica Norton 144 0,78 80/400

-4GB 299699 B6

Preparation Examples 5-6 Preparation of Catalysts

All procedures were similar to those in Preparation Example 1 except that the corresponding amounts of ruthemum nitrosyinitrate (Adrich, 1.5% Ru) were used. Norton 3177 (Preparation Example 5), respectively, was used as carrier. 6173 (Preparation Example 6). In these cases, the spraying / drying steps were repeated several times to obtain the desired metal content of 3 wt.

Example 1

A stainless steel 316 reactor (2.54 cm x 60 cm length) on a fully automatic pressure reaction system was charged with 50 g of the catalyst (cylindrical pellets 1/8) prepared in Preparation Example 1. After the leak test and nitrogen flushing, a stream of hydrogen at a flow rate of 1.6 x 10 ^-3 m ^{3 /} s was introduced into the reactor, increasing the temperature from room temperature to 300 ° C at 1 ° C / min. After maintaining the temperature at 300 ° C for 2 hours, the reactor was cooled to 150 ° C. Then, 10 wt. TICC in solvent at WHSV and pressure specified in Table II with twice excess hydrogen. Samples were taken each

4 hours in flow and analyzed by FID GC (60m x 0.25mm x 0.25 / grain / 3-DEX 120 column).

All data in Table E1 were taken at 100 hours in flow.

Table 11

Catalyst' T Pressure MPa WHSV Solvent iv ¹ Conversion Selek, to DHIQ Λ Prép-. Example 1 iio 9 ', 31 0.5 butyl acetate ioo 96.5 : Pr.ep. Example 1 120 10.3 2,0 butyl acetate 99, 0  , 0 Prep-. example. · 1 133 10., 3: 3.0 butyl acetate 100 ALIGN! 92.5 Prep. Example 1 14'5 5, 31 1, .5 butyl acetate 10.0 95.4 Prep. Example 1 150 6/07 ' 0 /, - butyl acetate : 9Q, - i 91, - 0 Prep. example .1 150 6.87 0> 5 heptane 9.0; ⁰ 89.7 Prep. - For example: 'T • 150 '  9.31 Q / 5 be those Tác tat 96, -7 91.5 Switch, example 1 150 9, -31 l ₇ 0 Butyl acetate: 100 ALIGN! 93.3 Prep ,. .example. 1 150 9.31 1, S butyl acetate Ioo 94.4 Prep. Example 1 16Ó 10.3 3.0 butyl acetate. ÍOO 90-, 0 Prep. Example 2 150 6.87 0.5 butyl acetate '95, 3 86.4 Prep. Example 3 15Ó 6.87 0.5 butyl acetate 98.0 86.1 Prep. Example: 4 140 9.31 1.5 butyl acetate 100 ALIGN! 92.6 Prep. Example 4 150 6.87 0.5 butyl acetate 96.3 90, 0 Prep. example 4 150 6; 37 0.5 Ethylacetate 95.7 90.5 Prep ,. example 4 · 450 9.31 04 5 butyl acetate 97.6 ’ 87, 1 Prep. Example 4 150 9.31 li 5 butyl acetate 'IOO 6.9,3; Prép. Example 5 150 6, 87: 0,5 ¹ butyl acetate 8'0 ,, .0: 87,5 ' Prep. example .6. 150 6.87 Oh, 5 ethyl acetate _94; 7 86.4 Prep. example. '6 150 .6. ·, 8 .7 0.5 isopropanol 95, 6 84.5

-5GB 299699 B6

Comparative Examples 1 - 4 (no controls)

Reaction tests were carried out in butyl acetate at 150 ° C. 6.87 MPa, and a WHSV value of 0.5 h ^_1 5 in the same manner as in Example 1 with the exception of the catalysts. The catalyst was a conventional commercial catalyst (Table III),

Table III

Cf. example Catalyst Conversion Selek, to DHIQ No .. · in

Cf. Example 1. Johnson · Maethey ’2% Řu / c 93.0 6 7 i 5 Cf. Example 2 _: Degussa / H2 ^r 5'7 2% Ru / alumina ,. '94, .9 83.0 Cf. example '3 batch. CC4 ^; -243 Chemicat 2 Ru / alundna ·, 77.5: 82.5 Cf. Example 4 batch. 456-67020 Johnson. Matthey 2 '% Ru /' QXI <d Silica 82.8 74.2

Example 2

The reaction was carried out in a similar reaction system to Example 1 using 150 g of catalyst prepared according to the method described in the evaporation of Example 1. 150 g of 3% Ru on Norton 3177 alumina was charged to a fixed bed reactor. After purging with nitrogen and reducing the catalyst at 300 ° C, a 10 wt. TICC in butylate at 150 ° C, 9.31 MPa, and a WHSV value of 1.0 h ^-1 . During the reaction, the pressure was maintained at

9.31 MPa, while temperature and WHSV were varied as shown in Fig. 1. This Fig. 1 is a graph illustrating the relationship between yield and flow time using a method and a catalyst in accordance with Example 2. As shown in Fig. 1, no inactivation was observed in more than 10 days. ......

After reaction for 200 hours, 41 liters of butyl acetate solution containing DHIQ (92.2% purity) was collected and placed in a 50-liter glass reactor dyed with a cooling system to obtain DHIQ crystals. After evaporation, 15 liters of n-heptane was added. Then the reactor was slowly cooled from 60 ° C to -10 ° C at a rate of 0.5 ° C / min. The yield of primary crystals was 73%. The procedure was repeated to obtain secondary crystals in 19% yield. The optical purity of the crystals was 99.5%,

Optical rotation [α] 20 = -72.6 melting point 114.3 ° C (coating 112-115 ° C).

The yield of this continuous hydrogenation process is higher than that of the earlier batch process, such as US 5,587,481 (yield 62-67%) and European patent application EP 0 751 128 (primary crystals 52.1 wt%, secondary crystals 20.7 wt%). .).

Many alternative embodiments and variations will be apparent to those skilled in the art.

Claims (5)

PATENT CLAIMS I. Process for the preparation of [3S- (3a, 4a, 8a, 8a)] - N-formyl-decahydro-3-isoehiocarbonylcarbamide from N-tert-butyl-1, 2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide with high optical yield, characterized in that N-tert-butyl-1,2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide is continuously reduced with hydrogen in organic solvent to [3S- (3a, 4a, [beta], 8a))] - N10 / [beta] -butyldecahydro-3-isoquinolinecarboxamide in a fixed bed reactor which is charged with a noble metal catalyst on an inorganic oxide carrier with a metal content range between 0.5 and 10% by weight, at a temperature in the range of 80 to 170 ° C, under a pressure in the range of 2.07 to 17.2 MPa and at a mass hourly space velocity in the range of 0.1 to 10 h ^-1 , and wherein the molecular ratio of hydrogen to N- tert -butyl-1,2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide is in the range of 4 to 10, The content of N- tert -butyl-1,2,3,4-tetrahydro-3 (S) -isoquinoline carboxamide in the organic solvent is in the range of 2 to 50% by weight, and the inorganic oxide carrier has a surface area according to Brunaueurer, Emmett & Keller in the range of 10 to 1000 m ² / g, a mean pore diameter of the pores is much smaller than 2.10 ^"8 mA total pore volume in the range from 0.2 to 1.2 cm ³ / g. The method of claim 1, wherein the pressure is in the range of 4 to 50 psi and the mean mass hourly space velocity is in the range of 0.2 to 6 hrs. 3. The process of claim 2 wherein the temperature is in the range 100-160 [deg.] C, the pressure is in the range 5.52 MPa to 11 MPa and the mean mass hourly space velocity is 25 in the range of 0.5 to 4 h ^-1 . A process according to claim 1 wherein the content of N-tert-butyl-1,2,3,4-tetrahydro-3 (S) -isoquinolinecarboxamide in the organic solvent is in the range of 5 to 30% by weight. The method of claim 1, wherein the organic solvent is at least one selected from the group consisting of acetic, propionic, lactic or isolactic acid, methanol, ethyl alcohol; n-propyl alcohol, isopropanol, n-butyl alcohol, n-butyl alcohol, tert-butyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, n-hexane, iso-hexane, n-heptane, iso-heptane, iso-heptane -octane and iso-octane. 6. The process of claim 5 wherein the organic solvent is at least one selected from isopropyl alcohol, tert-butyl alcohol, ethyl acetate, n-butyl acetate, n-hexane, and n-heptan. The process of claim 6 wherein the organic solvent is at least one selected from the group consisting of ethyl acetate, n-butyl acetate, n-hexane, and n-heptane. 8. The process of claim 1 wherein the noble metal is ruthenium or osmium. 45 '’ The method of claim 1, wherein the metal content is in the range of 1 to 6 wt%. 10. The process of claim 1 wherein the inorganic oxide carrier is 50 is selected from the group consisting of zalumines, silica alumina, oxide. zirconium, titanium oxide, and molecular sieves. II. 10. The method of claim 10 wherein the inorganic oxide carrier is alumina or silica. r ··: -7EN 299699 B6 Method according to claim 1, characterized in that the surface area according to Brunaueurer, Emmett & Keller of the inorganic oxidized carrier is between 20 and 500 m ² / g. Method according to claims 1-2, characterized in that the surface area according to Brunaueurera, Emnieíía & Kellera inorganic oxidized supports in the range of 50 and 300 m ² / g. The method of claim 1, wherein the total pore volume of the inorganic oxidized carrier is between 0.3 and 1.0 cm ³ / g. o, 15. The method of claim 1 wherein the solid bed reactor is a sprinkler bed reactor.