This invention relates to a method for- synthesis of biben- zyl systems with nitro groups as substituents. Such compounds are important intermediates for pharmaceuticals.

According to the method toluene derivateε with nitro groups, preferably in o- or p- position, are coupled oxidatively with air (oxygen) in methanolic KOH-solution under influence of small amounts of metal catalysts.

Several methods for the synthesis of nitrobibenzyl systems are known:

This method needs handling of KOtBu or NaOEt.The best yield, about 70 %, was reached by bubbling oxygen through the reac¬ tion mixture. The recovery of the product needs handling of ether and without equivalent amount of iso amyl formiate the yield will come down to 40 %. Using NaOMe about 55 % is obtained. KOtBu must be used in ether. The reaction time is long, about 24 hours at 0 C.

2/

30% KOH

Pure oxygen must be used. The yield is low, about 30 % Etylene diamine is a catalyst.

3/

Yields 51-60 %. The reaction time is short but large amounts of liquid ammonia must be used. NaNH_ is prepared in situ from NH_ . It is a drawback that natrium must be handled.

The earlier methods have several drawbacks as in certain cases bad yields, handling of chemicals with risks for the environment and comparatively expensive raw materials.

In the method according to the present invention more in¬ expensive raw materials are used, air is used in stead of oxygen and the catalysts are only used in small amounts. The method is superior to earlier methods as to economy as well as to safety.

To synthesis according to the present method can be illu¬ strated as follows:

Examples:o-Nitrotoluene,p-nitrotoluene

As metal catalysts metal acetonylacetonat, Me(AcAc)_, metal acetonylacetonate + crown ether, metal salt + crown ether or metal-tetraphenylporfin, (porfyrin type) are used.

r.et l -BcεtDnyl- Dibenz-1B-Croun-6-(crσwn ether) Bcεtonat e 2,3,11, 12-o'iben2D-1 _f 4,7,l0,l3,l6- hεxoxacyklooktsdEkE- 2,11-diene

f.e(porf ϊn) = ΠBIEI — tεtTe- f enylporf in

Tn the method inexpensive starting materials,suitable for full-scale production, as o-nitrotoluene,KOH,air and ca¬ talytic amounts of metal complex are used. Handling of Na or NaOET in technical scale is avoided as well as the handling of NaNH_. Oxygen is replaced by air (but it is possible to use oxygen)

The method will be further illustrated by the following non-limiting examples.

'Example 1

Preparation of 2,2 ' -dinitrobibenzyl

A catalytic amount of a metal catalyst (0,01 g metal porfin or 0,005 g metal (AcAc)~ + 0,01 g crown-ether) was added to a 33 % methanolic KOH-solution, (34 g KOH in 100 ml me¬ thanol) . The reaction mixture was cooled to 25 C, 2-nitro- toluene (13,7 g, 0,1 mol) was added and air was passed through the reaction mixture, the temperture of the reac¬ tion mixture being kept at 25°C. After 12 hours the pass- sing through of air was interrupted and 150 ml water and 50 ml methanol was added. The reaction mixture was fil¬ tered. The filter layer was dissolved in boiling toluene (bensene) , was filtered when hot, was cooled and was fut¬ tered again. Recrystallisation from ethanol gave a pro- duct with m.p. 120-121°C. Yield 24-27 %. As by-product o-nitrobenzoic acid was formed.

Example 2

Preparation of 4,4 '-dinitrobibenzyl from p-nitro-toluene The preparation was analogous to the previous example. Yield 91-99 %. M.p. 179-181°C.

Example 3

Preparation of 4,4 '-dichloro-2,2 '-dinitrotoluene from 2-nitro-4-chloro-toluene. The preparation was analogous to example 1. The product was precipitated fro toluene with petroleum ether. Yield 23 %. The IR-spectrum of the product was in accordance with the data of the literature.

The following table gives a summary of the performed expe¬ riments according to the method described above. The reac¬ tion time was 12 hours in all experiments and the ratio nitro.toluene/metal catalyst was 6.10 .

Tab le 1

Nitrotoluene Catalyst Yield% Product o-Nitrotoluene VO(AcAc) ₂ 8 2, 2 ' -Dinitrobibenzyl

II VO (AcAc) -,+crown ether 24

II VO(porfin) 26

II V0(porfin + cat amount H-.0- , (0,ig ⁾ 27

II No catalyst 0

II Ni(AcAc) ₂ 0

II Ni (porfin) 13 2, 2 ' -Dinitrobibenzyl

II Cu (Ac c) _+ crown ether 14

II Co (AcAc) ₂ + II 2

II Cr (AcAc) ₂ + II 12

II Fe (porfin)Cl 22

II FeCl- + crown ether 4

II TiCl ₃ + 1 0

II UD(AcAc) ₂ + II 0 p-Nitrotoluene VO(AcAc) ₂ 91 4,4 ' -Dinitrobibenzy

No catalyst 75 ^λ

II VO (porfin) 99

4-chloro 2nitro- 4,4 ' -dikloro-2 ,2 ' - toulene VO (porf in ) 23 dinitrobibenzyl c . -Ghloro- 4-nitro- 97 4, 4 ' -Dinitrotolan 2/ toluene

1/ From literature 2/ The reaction mixture is strongly alkaline and originally formed <*. -dichloro-4,4 '-dinitrobibenzyl will eliminate HCl and give 4,4'-dinitrotolan.

Also the following nitrosubstituted . toluenes were tested and gave the corresponding substituted bibenzyles in vary¬ ing yields:

2,6-dinitrotoluene,2,4-dinitrotoluene,2,4,6-trinitrotolue ne, 2-chloro-2-nitrotoluene,5-metoxi-2-nitrotoluene,6-chloro-2- nitrotoluene,2-chloro-4-nitrotoluene,3-metoxi-4-nitrotoluene .

In addition to the above mentioned catalysts also the follow¬ ing catalysts can be used for the syntheses according to the invention:

Ce(porfin) ,Pd(porfin)Pt(porfin,Hg(porfin),Zn(porfin) och Ti (porfin)

Methanolic KOH-solution can be replaced by methanolic NaOH- solution but as a rule the yield is lower.

The method according to this invention can be used with to- luene derivates having as substituents in the ring a nitro- group in o-or p-position. There may also be other substi¬ tuents in the ring as for example Cl,0CH-.,CH-. or other alkyl- groups.

Table 2 gives examples of further syntheses.

Table 2

Substituted Catalyst Yield Product toluene %

2-chloro-4- 2,2'dichloro-4,4' nitrotoluene VO (porf in) 99 dinitro-dibenzyl

II No catalyst 46 II

2-chloro-6-nitro- 2,2'-dichloro-6,6'- toluene VO (porf in 18 dinitro-bibenzyl

3-metoxi-4 3,3' -dimetoxi-4 , 4 ' - nitro-toluene 22 dinitro-bibenzyl

Fe ( porf in) Cl 14

2-Metoxi-4- 2,2' -Dimetoxi-4 , 4 ' nitrotoluene VO (porf in) 45 dinitrobibenzyl

Fe (porf in)Cl 36

5-Metoxi-4- nitrotoluene VO (porf in) 0 -