Valnemulin

101312-92-9,

launched 1999 novartis for bacterial infection

Valnemulin (trade name Econor) is a pleuromutilin antibiotic used to treat swine dysentery, ileitis, colitis and pneumonia. It is also used for the prevention of intestinal infections of swine.^[1] Valnemulin has been observed to induce a rapid reduction of clinical symptoms ofMycoplasma bovis infection, and eliminate M. bovis from the lungs of calves.^[2]

Pleuromutilin, a compound of formula

is a naturally occurring antibiotic, e.g. produced by the basidomycetes Pleurotus mutilus and P. passeckerianus, see e.g. The Merck Index, 12th edition, item 7694.

A number of further pleuromutilins having the principle ring structure of pleuromutilin and having e.g. antibacterial activity, have been developed.

A pleuromutilin of the present invention includes a pleuromutilin having the basic structural elements as set out in formula

wherein R is vinyl or ethyl and the dotted line is a bond or is no bond.

The following numbering system is used in the present application:

The dotted line between positions 19 and 20 (and between positions 1 and 2) is a bond or is no bond. In a compound of formula A or of formula PLEU a hydrogen atom in positions 4, 7 and/or 8 of the ring system may be replaced by deuterium, and if the dotted line between positions 1 and 2 is no bond (single bond between positions 1 and 2) the ring system may be further substituted in positions 1 and/or 2, e.g. by halogen, deuterium or hydroxy. The group —O— in position 14 is further substituted, preferably by a substituted carbonyl group.

Examples of pleuromutilins according to the present invention includes e.g.

• • A compound as disclosed in U.S. Pat. No. 3,716,579, e.g. of formula

• wherein R is CH₃—(CH₂)₇—CH═CH—(CH₂)₇—COO—, CH₃—(CH₂)₄—CH═CH—CH₂—CH═CH—(CH₂)₇—COO—, CH₃—(CH₂)₉—CH═CH—(CH₂)₇—COO— or hydrogen;
  • A compound as disclosed in GB1312148, e.g. of formula

14-Desoxy-14[(2-diethylaminoethyl)mercaptoacetoxy]mutilin, e.g. also known as tiamulin of formula 

 

• • A compound as disclosed in U.S. Pat. No. 4,130,709, e.g. of formula

 

• • A compound as disclosed in U.S. Pat. No. 4,129,721; e.g. of formula

and the 19,20-dihydro derivative thereof and the tetra(C_2-6)alkanoyl derivatives thereof;

• • A compound as disclosed in EP0013768, e.g. of formula

• • A compound as disclosed in EP0153277, e.g. an N-acyl-14-O-[(1-amino-2-methylpropan-2-yl)thioacetyl]-mutilin or 19,20-dihydromutilin, such as of formula

wherein R₁ is vinyl or ethyl positions 19 and 20), and R₂ is optionally hydroxy-substituted aminoalkyl or a 5-membered saturated heterocycle, e.g. including Valnemulin (Econor®) of formula

• • A compound as disclosed in U.S. Pat. No. 516,526, e.g. of formula

wherein R₁ and R₂ independently of each other are H, alkyl, alkenyl, cycloalkyl, aryl or aralkyl;

• • A compound as disclosed in WO9322288, e.g. of formula

wherein R₁ and R₂ are independently of each other H, alkyl, or, R₁ and R₂ together with the carbon atom to which they are attached are cycloalkyl; and R₃ and R₄ independently of each other are H, alkyl or substituted alkyl;

• • A compound as disclosed in WO9725309, e.g. of formula

wherein Y is carbamoyloxy, wherein the N-atom is unsubstituted or mono- or disubstituted, such as a compound of formula

see more at……..

• • A compound as disclosed in EP0153277, e.g. an N-acyl-14-O-[(1-amino-2-methylpropan-2-yl)thioacetyl]-mutilin or 19,20-dihydromutilin, such as of formula

wherein R₁ is vinyl or ethyl positions 19 and 20), and R₂ is optionally hydroxy-substituted aminoalkyl or a 5-membered saturated heterocycle, e.g. including Valnemulin (Econor®) of formula

• • A compound as disclosed in U.S. Pat. No. 516,526, e.g. of formula

wherein R₁ and R₂ independently of each other are H, alkyl, alkenyl, cycloalkyl, aryl or aralkyl;

• • A compound as disclosed in WO9322288, e.g. of formula

wherein R₁ and R₂ are independently of each other H, alkyl, or, R₁ and R₂ together with the carbon atom to which they are attached are cycloalkyl; and R₃ and R₄ independently of each other are H, alkyl or substituted alkyl;

• • A compound as disclosed in WO9725309, e.g. of formula

wherein Y is carbamoyloxy, wherein the N-atom is unsubstituted or mono- or disubstituted, such as a compound of formula

see more at…………….http://www.google.com/patents/US8088823

• Valnemulin is known from EP-0.153.277 and is described specifically therein in example 12.
  Valnemulin is also known by the commercial name Econor®.
• As is generally known, this compound has antibacterial properties, e.g. following oral or parenteral administration, and is used for the prevention or cure of a series of bacterial infections in the field of animal health. The broad spectrum of activity includes Streptococcus aronson, Staphylococcus aureus, Mycoplasma arthritidis, Mycoplasma bovigenitalium, Mycoplasma bovimastitidis, Mycoplasma bovirhinis,Mycoplasma sp., Mycoplasma canis, Mycoplasma felis, Mycoplasma fermentans, Mycoplasma gallinarum, Mycoplasma gallisepticum, A. granularum, Mycoplasma hominis, Mycoplasma hyorhinis,Actinobacillus laidlawii, Mycoplasma meleagridis, Mycoplasma neurolyticum, Mycoplasma pneumonia und Mycoplasma hyopneumoniae.
• WO 98/01127 describes its excellent activity against an illness complex that can arise whenever animals are kept in a very restricted space (increased stocking density) e.g. for transport purposes, and are thus exposed to great stress. The most frequent pathogens that play a decisive role in this instance are Mycoplasma hyopneumoniae, Serpulina(formerly Treponema) hyodysenteriae, Serpulina pilosicoli, Lawsonia intracellularis, Mycoplasma gallisepticum, Pasteurella multocida, Actinobacillus (Haemophilus) pleuropneumoniae and Haemophilus parasuis, whereby diseases of the respiratory tract and other infections often occur together and lead to a complex clinical picture. All herd animals are affected, e.g. cattle, sheep and pigs, but also poultry.
• In its free form (valnemulin base), valnemulin is relatively unstable and is therefore primarily used in the form of its salts, particularly as the hydrochloride. A current method of administering antibiotics in the field of animal health is the injection, since it is suitable for administering a controlled single dose and thus a quantity tailored to individual needs. This is often crucial to successful control of many infectious diseases in the field of animal medicines. In contrast, oral administration cannot be controlled nearly so well, and is more customary in human medicine.
• However, it has been shown that aqueous injection solutions and even oily injection suspensions of the salts of valnemulin are poorly tolerated by most domestic animals and in particular by pigs. Damage ranging from mild skin irritation to poorly healing necroses, has been observed. This is also one of the reasons that valnemulin has mainly been used orally until now. In addition, aqueous solutions usually do not show the desired depot action. A further problem is that valnemulin cannot be produced in technical quantities in the free form, as the so-called valnemulin base, but occurs as the salt, and has therefore been used for therapy as the salt.

………………………………….

syn

http://www.google.com/patents/CN102675173B?cl=en

valnemulin hydrochloride (Valnemulin hydrochloride) chemical name: [[2_ [[(2R) _2_ amino-3 – methyl-1 – oxobutyl] amino] -1,1 – dimethyl- ethyl] thio] acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, I OR) -6 – vinyl-decahydro-5 – hydroxy -4,6,9,10 – tetramethyl-1 – oxo _3a, 9 – propanol _3aH_ cyclopenta cyclooctene en-8 – yl ester hydrochloride, the chemical structure of formula I as shown. A molecular weight of 601.28, as a white amorphous powder characters have strong hygroscopicity, soluble in water, ethanol, methyl tert-butyl ether in almost insoluble, mp 174-177Ό.

Valnemulin hydrochloride is a new generation of pleuromutilins semi-synthetic antibiotics, are two terpenes, and tiamulin belong to the same class of drugs that are animal-specific antibiotics. Mainly used for prevention and treatment of pigs, cattle, sheep and poultry mycoplasma disease and Gram-positive bacterial infections. 1999 by the European Commission approved for the prevention and treatment of swine dysentery swine dysentery infection caused by the spirochete short and swine enzootic pneumonia caused by the Mycoplasma pneumoniae infection is the first Europe-wide approval of veterinary drugs premixes, is as a veterinary prescription drugs. September 9, 2010, approved by the Ministry of Agriculture Bulletin No. 1457 of Valnemulin hydrochloride developed materials and premixes for the state Department of Agriculture approved new animal drug II. Therefore, in our veterinary clinic has broad application prospects.

 Chemical synthesis of hydrochloric Valnemulin has a lot of literature. Most of which are to pleuromutilins as raw material, p-toluenesulfonyl chloride sulfonation reaction with dimethyl cysteamine hydrochloride, and then protected with an amino group, a carboxyl group is activated D-valine reaction, the final hydrolysis Valnemulin hydrochloride.

Chinese patent discloses a method for preparing CN102225905A Valnemulin hydrochloride method, which is after the Pleuromutilin reacted with tosyl chloride, after 1 – amino-2 – methyl-2 – thiolate substituted acid to give (2 – amino-1 ,1 – dimethylethyl) thio] acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R) -6 – vinyl decahydro _5_ hydroxy -4,6,9,10 – tetramethyl-1 – oxo-3a, 9 – propanol _3aH_ cyclopenta cyclooctene – (4H) -8 spare ester; other with D- valine methyl acetoacetate and the reaction with chloroacetic acid anhydride as isobutyl, and then with (2 – amino-1 ,1 – dimethylethyl) thio] acetic acid (3aS, 4R, 5S, 6S, 8R , 9R, 9aR, I OR) -6 – vinyl decahydro-5 – hydroxy -4,6,9,10 – tetramethyl _1_ oxo _3a, 9 – propanol _3aH_ garrison diene ring and cyclooctene – (4H) -8 ester amide hydrochloride later deprotected valnemulin hydrochloride was obtained, with ether as the solvent for this process, morpholine catalyst. In this line, the spent acid to activate Dioxide valine carboxy, increasing the difficulty of activation, and in the last reaction step using ether as the solvent, low-boiling inflammable volatile ether, in the operation increased risk. [0007] Chinese patent CN101318921A also opened a method for preparing Valnemulin, comprising the following steps: (1) preparation of chlorinated Pleuromutilin: to Pleuromutilin as raw materials, the reaction with HCl, convert it to Chloride pleuromutilin; (2) Preparation of N-allyloxycarbonyl group of valine: valine as starting material, which was reacted with allyl chloroformate to obtain N-protected amino group is allyloxycarbonyl group valine; (3) 1,1 – dimethyl-2 – Preparation of (N-allyloxycarbonyl group valinamido) ethanethiol: N-allyloxycarbonyl group of valine obtained acid chloride with oxalyl chloride and _ chloride with 1,1-dimethyl-2 – aminoethanethiol intermediate obtained by reacting 1,1 – dimethyl -2 – (N-allyloxycarbonyl group valinamido) ethanethiol; (4) Preparation of valnemulin of: 1,1 – dimethyl -2 – (N-allyloxycarbonyl group valinamido) reaction with ethanethiol pleuromutilins chloride to obtain an amino protected valnemulin In palladium catalyzed hydrogenation of carbon was going to protect Valnemulin. The disadvantage of this method is the use of a pleuromutilin in the chloride solution of HCl in methanol, increased corrosion of the equipment; allyl protecting group removal in the spent catalyst is palladium on carbon, palladium on carbon is too high and difficult recovery rates , thereby increasing the cost of the final product.

Starting materials Pleuromutilin by higher fungi Basidiomycetes Pleurotus a strain produced by submerged culture mainly against Gram-positive bacteria and mycoplasma active antimicrobial substances. As a semi-synthetic precursor substance, its content and impurities have a significant impact on the synthesis of hydrochloric acid Valnemulin quality standards. Recrystallization can effectively remove impurities and improve the content, thus effectively simplify the purification process to remove impurities and hydrochloric La Vergne wonderful forest to provide a guarantee from the source.

 Example 1:

 A Valnemulin hydrochloride chemical synthesis method, as follows:

 (I) purified pleuromutilin

[0021] 250g of pleuromutilin first dissolved in methyl tert-butyl ether 2000mL stirred solution clear. Activated carbon was then added 50g, stirred for 3 h at room temperature decolorization, activated carbon was filtered off and the filtrate was concentrated to about 500mL heating when a large number of crystal precipitation, heating was stopped, cooled to room temperature and stirring was continued for 4h. After the crystals were centrifuged and dried to obtain fine pleuromutilin 220g (yield 88%).

References