GB1564043A - Manufacture of n-(3,4-dimethylphenyl)-d-ribamine - Google Patents

Manufacture of n-(3,4-dimethylphenyl)-d-ribamine Download PDF

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GB1564043A
GB1564043A GB5348976A GB5348976A GB1564043A GB 1564043 A GB1564043 A GB 1564043A GB 5348976 A GB5348976 A GB 5348976A GB 5348976 A GB5348976 A GB 5348976A GB 1564043 A GB1564043 A GB 1564043A
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dimethylphenyl
ribamine
catalyst
yield
bars
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BASF SE
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BASF SE
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Priority claimed from DE19752558516 external-priority patent/DE2558516C3/en
Priority claimed from DE19752558515 external-priority patent/DE2558515C3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
    • C07D475/14—Benz [g] pteridines, e.g. riboflavin

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

N-[3,4-Dimethylphenyl]-D-ribamine of the formula I is prepared by catalytic hydrogenation of a mixture of 3,4-dimethylaniline and/or 3,4-dimethylnitrobenzene and a D-ribonic acid derivative or of D-ribonic acid 3,4-dimethylanilide. The hydrogenation takes place in an inert solvent at temperatures of above 100 and up to 155 DEG C. The compound obtained is an intermediate for the preparation of vitamin B2. <IMAGE>

Description

(54) MANUFACTURE OF N-F34-DlMETHYLPHENYL]-D- RIBAMINE (71) We, BASF AKTIENGESELL SCHAFT, a German Joint Stock Company of 6700 Ludwigshafen, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to the manufacture of N - [3,4 - dimethylphenyl] - D ribamine, which has the formula I
N - [3,4 - Dimethylphenyl] - D - ribamine, an important intermediate for the manufacture of vitamin B2, may be manufactured, for example in accordance with a process dis dosed in U.S. Patent 2,384,105, by reacting D - ribose and 3,4 - dimethylaniline and catalytically hydrogenating the product at up to 100"C. Since D-ribose is difficult to obtain, U.S. Patent 2,411,611 provides a process in which 3,4 - dimethylaniline is condensed with D - ribonic acid y - lactone to give D - ribonic acid, 3,4 - dimethylanilide, from which latter component N - [3,4 - dimethylphenyl] - D ribamine is then produced by acetylating, chlorinating, hydrogenating and desacetylating. This involved process does not permit economical manufacture of N - [3,4 - dimethylphenyl] - D - ribamine.
It has also already been proposed to hydrogenate a mixture of 3,4 - dimethylaniline or of the corresponding nitro compound with D - ribonic acid y - lactone in an inert solvent, using platinum oxide. In this process, disclosed in U.S. Patent 2,422,997( which is carried out at below 1000C to avoid sidereactions, N - [3,4 - dimethylphenyl) - D - ribamine is obtained in moderate yields.
The present invention seeks to provide a process for the manufacture of N - [3,4 dimethylphenyl] - D - ribamine which permits manufacture of this important vitamin intermediate by a very simple method, and in good yield and high purity.
We have found that N - [3,4 - dimethylphenyl] - D - ribamine can be manufactured in an advantageous manner if (a) a mixture of 3,4 - dimethylaniline and/ or 3,4 - dimethylnitrobenzene with a D ribonic acid compound of the general formula II
where each R' is hydrogen or one of the R's together with R" is a single bond, R" is hydroxyl, OR"' or, together with R', a single bond, and R"' is a hydrocarbon radical of 1 to 10 carbon atoms which may or may not be substituted by one or more hydroxyl groups, or (b) D - ribonic acid 3,4 - dimethylanilide, which has the formula III
is catalytically hydrogenated in an inert solvent at from above 1000C to 1550C, at a hydrogen pressure of from 1 to 1,000 bars.
The starting compounds of the formula II are lactones of D - ribonic acid, D - ribonic acid itself and esters thereof. The alcohol radicals OR"' may be straight-chain or branched, saturated or unsaturated by hydro carbon radicals of 1 to 10, preferably of 1 to 5, carbon atoms, which may or may not be substituted by one or more hydroxyl groups.
Examples of radicals R"' are alkyl, e.g. methyl or butyl. D - Ribonic acid 7 - lactone is the preferred starting compound.
D - Ribonic acid 3,4 - dimethylanilide for use as a starting compound is readily obtainable, for example by reacting D - ribonic acid 7 - lactone with 3,4 - dimethylaniline (J. Org.
Them. 166 (1945)).
Conventional organic solvents which undergo no significant change, or no change at all, under the reaction conditions may be used as the inert solvent for the hydrogenation. Examples are alcohols, e.g. methanol, ethanol, propanol and butanol, and ethers, e.g. dioxane, the last-mentioned being the preferred solvent.
Examples of catalysts which may be used for the catalytic hydrogenation are transition metals, e.g. copper, chromium, nickel, iron, platinum, palladium, rhodium, cerium, thorium and zinc, as well as aluminum and magnesium metals, and the oxides of the said metals.
Mixtures of the above metals or metal oxides, such as the mixed oxides mentioned in Schwab: "Handbuch der Katalyse", volume 5, pages 567-577, are also very suitable.
Catalysts containing copper oxide and/or copper, especially those containing finely divided copper oxide and/or copper on a catalyst carrier, have proved particularly advantageous. Examples of carriers present in such catalysts are refractory oxides, e.g. chromium oxide, aluminum oxide or cerium oxide.
Such catalysts are described, for example, by H. Adkins in Organic Reactions, volume VIII, 1954, pages 8 and 9, and in German Laid Open Application DOS 2,024,282. Amongst these catalysts, those containing copper oxide and chromium oxide and those containing copper oxide and aluminum oxide are particularly suitable.
It is particularly advantageous to treat the catalyst with hydrogen before it is used in the hydrogenation according to the invention. This pre-hydrogenation is effected, for example, at up to 400or preferably at from 150 to 250cm, under a hydrogen pressure of from 0.01 to 300 bars.
The hydrogenation according to the invention is carried out at from above 100 to 155at, preferably at from 125 to 1450C. The hydrogen pressure is from 1 to 1,000 bars, preferably from 100 to 300 bars. The starting materials are advantageously reacted in the stoichiometric ratio. It is advantageous to use from 100 to 400 parts by weight of solvent, based on 100 parts by weight of the mixture of starting materials.
The process of the invention gives pure N - [3,4 - diinethylphenylj - D - ribamine in good yield. This advantageous outcome is surprising, since it had previously been assumed that hydrogenation of a mixture of 3,4 - dimethylaniline and D - ribonic acid y - lactone at above 1000C did not give any N - [3,4 - dimethylphenylj - D - ribamine (J. Amer. Chem. Soc. 68, (1946)1,777). In addition, epimerization, with formation of D arabonic acid 3,4 - dimethylanilide had to be feared (J. Chem. Soc. 165 (1945)).
EXAMPLE 1 A solution of 29.6 g (0.2 mole) of D ribonic acid y - lactone and 24.2 g (0.2 mole) of 3,4 - dimethylaniline in 150 ml of dioxane is thoroughly mixed with 18 g of pre-hydrogenated copper oxide/chromium oxide catalyst, containing barium, and hydrogenated, in a hydrogenation autoclave, at 1350C under a hydrogen pressure of 250 bars for 32 hours.
After the hydrogenation has ended and the mixture has been cooled, 250 ml of ethanol are added and the batch is heated to dissolve the N - [3,4 - dimethylphenylj - D - ribamine which has partially precipitated. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from ethanol.
Yield: 62% of N - [3,4 - dimethylphenyl]- D - ribamine.
Melting point: 1370C; [2g]D=21.94 (C=0.4; methanol) Molecular weight=255.3 1 Analysis: C1,H21NO4 %C %H %O %N found: 61.2 8.1 25A 5.5 calculated: 61.15 8.29 25.07 5.49 13C NMR-spectrum (DDMSO; TMS standards) Chemical shift (ppm):147.2; 136.1; 129.8; 122.0; 114.2; 110.0; 73.5; 72.8; 70.4; 63.3; 46.2; 19.6; 18.3.
In order to pre-hydrogenate the catalyst, 18 g of copper oxide/chromium oxide catalyst in 150 ml of dioxane are treated, at 2000C. with hydrogen under a pressure of 200 bars for 1 hour, with good mixing.
The copper oxide/chromium oxide catalyst pre-hydrogenated in this way is introduced into the hydrogenation autoclave whilst excluding air, and is immediately employed for the hydrogenation.
The procedure employed in the Examples which follow is as described in Example 1.
For this reason, only differences from the pro cedure described are mentioned.
EXAMPLE 2 Catalyst: 18 g of a pre-reduced copper oxide/aluminum oxide catalyst which has been obtained by heating a compound having the composition Cu6Al2(COs)(OH)1s . 4H20.
Time: 9 hours Yield: 72% Melting point: 1380C.
The IR spectrum, 13C NMR-spectrum and analysis confirm the structure of N - [3,4 dimethylphenyl] - D - ribamine.
[a]D=--22.30 (C=0.41 methanol).
The catalyst is pre-hydrogenated by passing a stream of hydrogen over 18 g of copper oxide/aluminum oxide catalyst for 12 hours in an oven at 200 C.
EXAMPLE 3 Temperature: 1400C Yield: 56% Melting point 136"C.
EXAMPLE 4 Temperature: 1300C Yield: 71% Melting point: 1400C [a]D=22.4 (C=0.39; methanol) EXAMPLE 5 Instead of 3,4 - dimethylaniline, 0.2 mole of 3,4 - dimethylnitrobenzene is employed.
Hydrogenation: 24 hours at room ternperature under 80 bars hydrogen pressure, followed by 15 hours at 1400C under 240 bars hydrogen pressure.
The yield of N - [3,4 - dimethylphenyl] D - ribamine is somewhat lower than in Example 1.
EXAMPLE 6 12 g of pre-hydrogenated copper oxide/ chromium oxide catalyst Yield: EXAMPLE 7 Solvent used for the hydrogenation: methanol.
The yield is somewhat lower than in Example 1.
EXAMPLE 8 Batch: 44.4 g (0.3 mole) of D - ribonic acid y - lactone and 24.2 g (0.2 mole) of 3,4- dimethylaniline.
15 hours hydrogenation at 300 bars H, and 135 C.
Yield: 60%.
EXAMPLE 9 18. g of copper oxide/chromium oxide catalyst are pre-hydrogenated for 1 hour in 150 ml of dioxane at 2000C under 200 bars hydrogen pressure. 53.9 g (0.2 mole) of D - ribonic acid 3,4 - dimethylanilide are hydrogenated with the fresh pre-hydrogenated copper oxide/chromium oxide catalyst for 36 hours at 1350C under 300 bars hydrogen pressure, with good mixing. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from ethanol.
Yield: 50% of N - [3,4 - dimethylphenyl) D-n'bamine.
Melting point: 1380C; [aj=-21.80C (C=0.4; methanol) Analysis: C1,H21NO4 Molecular weight=255.31 ,oC oH t'O̳ s;N found: 61.2 8.1 25.4 5.5 calulated: 61.15 8.29 25.07 5.49 13C NMR-spectrum (DDMSO; TMS standards) Chemical shift (ppm): 147.2; 136.1; 129.8; 122.9; 114.2; 110.0, 73.5; 72.8; 70.4; 63.3; 46.2; 19.6; 18.3.
The IR spectrum proves the structure of N - [3,4 - dimethylphenyl] - D - ribamine.
WHAT WE CLAIM IS: 1. A process for the manufacture of N [3,4 - dimethylphenyl] - D - ribamine, which has the formula I
wherein a mixture of 3,4 - dimethylaniline and/or 3,4 - dimethylnitrobenzene with a D - ribonic compound of the general formula II *
where each R' is hydrogen or one of the R's together with R" is a single bond, R" is hydro::::yl, OR"' or, together with R', a single bond, R"' is a hydrocarbon radical of 1 to 10 carbon atoms which may or may not be substituted by one or more hydroxyl groups, is catalytically hydrogenated in an inert solvent at from above 1000C to 1550C at a hydrogen pressure of from 1 to 1,000 bars.
2. A modification of the process claimed in claim 1, wherein there is used, instead of the mixture of 3,4 - dimethylaniline and/or 3,4 - dimethylnitrobenzene with a Dribonic compound of the general formula II, D - ribonic acid 3,4 - dimethylanilide, which has the formula III
3. A process as claimed in claim 1 or 2, wherein the hydrogenation is carried out using a catalyst which contains copper oxide and/or copper.
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (11)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    The IR spectrum, 13C NMR-spectrum and analysis confirm the structure of N - [3,4 dimethylphenyl] - D - ribamine.
    [a]D=--22.30 (C=0.41 methanol).
    The catalyst is pre-hydrogenated by passing a stream of hydrogen over 18 g of copper oxide/aluminum oxide catalyst for 12 hours in an oven at 200 C.
    EXAMPLE 3 Temperature: 1400C Yield: 56% Melting point 136"C.
    EXAMPLE 4 Temperature: 1300C Yield: 71% Melting point: 1400C [a]D=22.4 (C=0.39; methanol) EXAMPLE 5 Instead of 3,4 - dimethylaniline, 0.2 mole of 3,4 - dimethylnitrobenzene is employed.
    Hydrogenation: 24 hours at room ternperature under 80 bars hydrogen pressure, followed by 15 hours at 1400C under 240 bars hydrogen pressure.
    The yield of N - [3,4 - dimethylphenyl] D - ribamine is somewhat lower than in Example 1.
    EXAMPLE 6
    12 g of pre-hydrogenated copper oxide/ chromium oxide catalyst Yield: EXAMPLE 7 Solvent used for the hydrogenation: methanol.
    The yield is somewhat lower than in Example 1.
    EXAMPLE 8 Batch: 44.4 g (0.3 mole) of D - ribonic acid y - lactone and 24.2 g (0.2 mole) of 3,4- dimethylaniline.
    15 hours hydrogenation at 300 bars H, and 135 C.
    Yield: 60%.
    EXAMPLE 9 18. g of copper oxide/chromium oxide catalyst are pre-hydrogenated for 1 hour in 150 ml of dioxane at 2000C under 200 bars hydrogen pressure. 53.9 g (0.2 mole) of D - ribonic acid 3,4 - dimethylanilide are hydrogenated with the fresh pre-hydrogenated copper oxide/chromium oxide catalyst for 36 hours at 1350C under 300 bars hydrogen pressure, with good mixing. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from ethanol.
    Yield: 50% of N - [3,4 - dimethylphenyl) D-n'bamine.
    Melting point: 1380C; [aj=-21.80C (C=0.4; methanol) Analysis: C1,H21NO4 Molecular weight=255.31 ,oC oH t'óO s;N found: 61.2 8.1 25.4 5.5 calulated: 61.15 8.29 25.07 5.49 13C NMR-spectrum (DDMSO; TMS standards) Chemical shift (ppm): 147.2; 136.1; 129.8; 122.9; 114.2; 110.0, 73.5; 72.8; 70.4; 63.3; 46.2; 19.6; 18.3.
    The IR spectrum proves the structure of N - [3,4 - dimethylphenyl] - D - ribamine.
    WHAT WE CLAIM IS: 1. A process for the manufacture of N [3,4 - dimethylphenyl] - D - ribamine, which has the formula I
    wherein a mixture of 3,4 - dimethylaniline and/or 3,4 - dimethylnitrobenzene with a D - ribonic compound of the general formula II *
    where each R' is hydrogen or one of the R's together with R" is a single bond, R" is hydro::::yl, OR"' or, together with R', a single bond, R"' is a hydrocarbon radical of 1 to 10 carbon atoms which may or may not be substituted by one or more hydroxyl groups, is catalytically hydrogenated in an inert solvent at from above 1000C to 1550C at a hydrogen pressure of from 1 to 1,000 bars.
  2. 2. A modification of the process claimed in claim 1, wherein there is used, instead of the mixture of 3,4 - dimethylaniline and/or 3,4 - dimethylnitrobenzene with a Dribonic compound of the general formula II, D - ribonic acid 3,4 - dimethylanilide, which has the formula III
  3. 3. A process as claimed in claim 1 or 2, wherein the hydrogenation is carried out using a catalyst which contains copper oxide and/or copper.
  4. 4. A process as claimed in claim 1 or 3.
    wherein a mixture of 3,4 - dimethylaniline and/or 3,4 - dimethylnitrobenzene with D ribonic acid y - lactone, as the compound of general formula II, is catalytically hydrogenated.
  5. 5. A process as claimed in any of claims 1 to 4, wherein dioxane is used as the inert solvent.
  6. 6. A process as claimed in any of claims 1 to 5, wherein the catalyst is treated with hydrogen at up to 4000C under a hydrogen pressure of 0.01 to 300 bars prior to use in the catalytic hydrogenation.
  7. 7. A Drocess as claimed in any of claims 1 to 6, wherein the catalytic hydrogenation is carried out at 125 to 1450C.
  8. 8. A process as claimed in any of claims 1 to 7, wherein a catalyst comprising copper oxide and either chromium oxide or aluminum oxide is used.
  9. 9. A process for the manufacture of N [3,4 - dimethylphenyl] - D - ribamine carried out substantially as described in any of the foregoing Examples.
  10. 10. N - [3,4 - dimethylphenyl] - R ribamine when manufactured by a process as claimed in any of claims 1 to 9.
  11. 11. Vitamin B2 when made from N - [3,4 dimethylphenyl] - D - ribamine as claimed in claim 10.
GB5348976A 1975-12-24 1976-12-22 Manufacture of n-(3,4-dimethylphenyl)-d-ribamine Expired GB1564043A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19752558516 DE2558516C3 (en) 1975-12-24 1975-12-24 Process for the preparation of N- [3,4-dimethylphenyl] D-ribamine
DE19752558515 DE2558515C3 (en) 1975-12-24 1975-12-24 Process for the preparation of N- [3,4-dimethylphenyl] D-ribamine

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JP (1) JPS5283339A (en)
CH (1) CH623300A5 (en)
FR (1) FR2336377A1 (en)
GB (1) GB1564043A (en)
HU (1) HU174889B (en)
NL (1) NL7614211A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2650232A1 (en) * 1976-11-02 1978-05-11 Basf Ag Process for the preparation of amines
DE2650830A1 (en) * 1976-11-06 1978-05-11 Basf Ag METHOD OF MANUFACTURING ANGULAR CLAMP ON 3,4-DIMETHYLPHENYL ANGLE CLAMP TO -D-RIBAMINE

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CH623300A5 (en) 1981-05-29
JPS5283339A (en) 1977-07-12
HU174889B (en) 1980-04-28
FR2336377B1 (en) 1980-10-17
NL7614211A (en) 1977-06-28
FR2336377A1 (en) 1977-07-22

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