25775-90-0

Usage

Uses

Used in Pharmaceutical Industry:
(Z)-CAPSAICIN is used as a topical analgesic for the treatment of severe pain in adults with osteoarthritis of the knee. It is used in conjunction with oral COX-2 inhibitors or NSAIDs to provide effective pain relief.
Used in Neurobiological Research:
(Z)-CAPSAICIN is used as a tool in neurobiological research, acting as a prototype vanilloid receptor agonist. This allows researchers to study the effects and mechanisms of action of capsaicin and related compounds on the transient receptor potential vanilloid type 1 (TRPV1) channel, which plays a crucial role in pain perception and other physiological processes.

Originator

E Merck AG (Germany)

Clinical Use

Zucapsaicin, the cis-isomer of the natural product capsaicin, is a topical analgesic that was initially developed by Winston Pharmaceuticals and approved in Canada in July 2010 for the treatment of severe pain in adults with osteoarthritis of the knee. The advantages of zucapsaicin compared with naturally-occurring capsaicin are reported to be a lesser degree of local irritation (stinging, burning, erythema) in patients and a greater degree of efficacy in preclinical animal models of pain. The analgesic action of both zucapsaicin and capsaicin is mediated through the transient receptor potential vanilloid type 1 (TRPV1) channel, a ligand-gated ion channel expressed in the spinal cord, brain, and localized on neurons in sensory projections to the skin, muscles, joints, and gut.

Synthesis

The scale preparation of zucapsaicin likely parallels the original approach described by Gannett and co-workers involving the coupling of vanillylamine with (Z)-8-methylnon-6-enoyl chloride. 216 Orito and co-workers elaborated this original approach in an effort to prepare both capsaicin and zucapsaicin on gram-scale, and this route is described in the scheme. Commercial 6-bromohexanoic acid (285) was activated as the Wittig salt prior to condensation with isobutylaldehyde in the presence of strong base to generate an 11:1 ratio of E/Z-olefinic acids favoring Z-isomer 286. Removal of the minor isomer was easily achieved by short-path distillation.217 Interestingly, the authors reported that facile olefin isomerization of 286 occurred upon exposure to nitric acid at elevated temperatures, converting 286 to the corresponding E-isomer. Recrystallization provided the product on multi-gram scale in 77% yield, representing a possible scale production method for capsaicin. For the preparation of zucapsaicin, acid 286 was converted the acid chloride via thionyl chloride followed by immediate condensation with commercially available vanillylamine (287). Two recrystallization steps were subsequently employed to produce gram-scale amounts of zucapsaicin (XXVI) in 66% yield overall for the two-step process.

InChI:InChI=1/C18H27NO3/c1-14(2)8-6-4-5-7-9-18(21)19-13-15-10-11-16(20)17(12-15)22-3/h6,8,10-12,14,20H,4-5,7,9,13H2,1-3H3,(H,19,21)/b8-6+

Synthetic route

Vanillylamin (1196-92-5) + (Z)-8-Methyl-non-6-enoyl chloride (31467-61-5) → cis-capsaicin (25775-90-0)

Conditions	Yield
In diethyl ether; N,N-dimethyl-formamide	70%
In diethyl ether for 72h; Ambient temperature;
In diethyl ether 1.) room temp., 2 h, 2.) reflux, 2 h; Yield given;
In tert-butyl methyl ether at 20 - 40℃; for 4h;	5.42 g

(6Z)-8-methyl-6-nonaneneoic acid (31467-60-4) → cis-capsaicin (25775-90-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl chloride / 3 h 2: 70 percent / dimethylformamide; diethyl ether View Scheme
Multi-step reaction with 2 steps 1: thionyl chloride / 1.) RT, 8 h, 2.) 100 deg C, 0.5 h 2: diethyl ether / 1.) room temp., 2 h, 2.) reflux, 2 h View Scheme
Multi-step reaction with 2 steps 1: thionyl chloride / 1.) RT, 18 h, 2.) 100 deg C, 30 min 2: diethyl ether / 72 h / Ambient temperature View Scheme

(5-carboxypentyl)triphenylphosphonium bromide (50889-29-7) → cis-capsaicin (25775-90-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: t-BuOK / dimethylformamide / 15 h / Ambient temperature 2: thionyl chloride / 1.) RT, 8 h, 2.) 100 deg C, 0.5 h 3: diethyl ether / 1.) room temp., 2 h, 2.) reflux, 2 h View Scheme

vanillin (121-33-5) + KOH-solution → cis-capsaicin (25775-90-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium formate / 3 h / 180 °C 2: diethyl ether / 1.) room temp., 2 h, 2.) reflux, 2 h View Scheme

hexahydro-2H-oxepin-2-one (502-44-3) → cis-capsaicin (25775-90-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: conc. H2SO4 / Heating 2: pyridinium chlorochromate (PCC), sodium acetate / CH2Cl2 / 1.5 h / Ambient temperature 3: 1.) t-BuOK / 1.) DMF, RT, 5 min, 2.) a) RT, 20 h, b) 90 deg C, 1 h 4: aq. KOH / ethanol / 1 h / Heating 5: thionyl chloride / 1.) RT, 18 h, 2.) 100 deg C, 30 min 6: diethyl ether / 72 h / Ambient temperature View Scheme

methyl 6-oxohexanoate (6654-36-0) → cis-capsaicin (25775-90-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) t-BuOK / 1.) DMF, RT, 5 min, 2.) a) RT, 20 h, b) 90 deg C, 1 h 2: aq. KOH / ethanol / 1 h / Heating 3: thionyl chloride / 1.) RT, 18 h, 2.) 100 deg C, 30 min 4: diethyl ether / 72 h / Ambient temperature View Scheme

di-tert-butyl dicarbonate (24424-99-5) + t-butyldimethylsiyl triflate (69739-34-0) + cis-capsaicin (25775-90-0) → (Z)-tert-butyl 4-(tert-butyldimethylsilyloxy)-3-methoxybenzyl(8-methylnon-6-enoyl)carbamate

Conditions	Yield
Stage #1: t-butyldimethylsiyl triflate; cis-capsaicin With triethylamine In dichloromethane at 0 - 22℃; for 0.5h; Stage #2: di-tert-butyl dicarbonate With dmap In dichloromethane; acetonitrile at 22℃; for 1h;	76%

cis-capsaicin (25775-90-0) → dihydrocapsaicin (19408-84-5)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethanol under 760 Torr; for 4h;

cis-capsaicin (25775-90-0) → (Z)-tert-butyl 4-(tert-butyldimethylsilyloxy)-3-methoxybenzyl(8,8,8-trifluorooct-6-enoyl)carbamate

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0.5 h / 0 - 22 °C 2: dmap / acetonitrile / 1 h / 22 °C 3: C47H71ClMoN2O / benzene / 4 h / 22 °C / Glovebox; Inert atmosphere View Scheme

cis-capsaicin (25775-90-0) → (Z)-tert-butyl 4-(tert-butyldimethylsilyloxy)-3-methoxybenzyl(8-methylnon-6-enoyl)carbamate

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0.5 h / 0 - 22 °C 2: dmap / acetonitrile / 1 h / 22 °C View Scheme

t-butyldimethylsiyl triflate (69739-34-0) + cis-capsaicin (25775-90-0) → C24H41NO3Si

Conditions	Yield
With triethylamine In dichloromethane at 0 - 22℃; for 0.5h;

Upstream product

• 1196-92-5 Vanillylamin 
• 31467-61-5 (Z)-8-Methyl-non-6-enoyl chloride 
• 4547-43-7 methyl 6-hydroxycaproate 
• 148999-69-3 (6-methoxy-6-oxohexyl)triphenylphosphonium bromide 
• 112375-42-5 methyl (6Z)-8-methylnon-6-enoate 
• 6654-36-0 methyl 6-oxohexanoate 
• 502-44-3 hexahydro-2H-oxepin-2-one 
• 31467-60-4 (6Z)-8-methyl-6-nonaneneoic acid 
• 121-33-5 vanillin 
• 50889-29-7 (5-carboxypentyl)triphenylphosphonium bromide 

Downstream Products

• 19408-84-5 dihydrocapsaicin 

Relevant academic research and scientific papers

Preparation method of zucapsaicin and its intermediate

The invention discloses a preparation method of zucapsaicin and its intermediate. The invention provides a preparation method of zucapsaicin I. The preparation method comprises that a zucapsaicin intermediate IV and a dialkylborane reducing agent in an organic solvent in the presence of a catalyst undergo a reduction reaction to produce zucapsaicin I. The preparation method is simple and safe in operation, the reaction is easy to monitor, the zucapsaicin I product has high purity, a total yield is high, a production cost is low and the preparation method is suitable for industrial production.

Vanilloids. 1. Analogs of Capsaicin with Antinociceptive and Antiinflammatory Activity

As part of a program to establish structure-activity relationships for vanilloids, analogs of the pungent principle capsaicin, the alkyl chain portion the parent structure (and related compounds derived from homovanillic acid) was varied.In antinociceptive and antiinflammatory assays (rat and mouse hot plate and croton oil-inflamed mouse ear), compounds with widely varying alkyl chain structures were active.Short-chain compounds were active by systemic administration in the assays mentioned above but they retained the high pungency and acute toxicity characteristic of capsaicin.In contrast, the long chain cis-unsaturates, NE-19550 (vanillyloleamide) and NE-28345 (oleylhomovanillamide), were orally active, less pungent, and less acutely toxic than capsaicin.The potential of these compounds as antiinflammatory/analgesic agents is discussed in light of recent data on the mechanism of action of vanilloids on sensory nerve fibers.

The Capsaicinoids: Their Separation, Synthesis, and Mutagenicity

Capsaicin (1b), the pungent ingredient in many varietes of Capsicums has recently been implicated as a possible carcinogen.When obtained from natural sources 1b is always accompanied by a number of related homologues.We have isolated seven of these homologues, characterized them, and synthesized them by a general and unique route developed in our laboratories.Also reported are mutagenicity data for 1b and an extract of red pepper as measured by the Ames assay and the V-79 mammalian cell assay.