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SINEFRIN
CAS NO: 94-07-5
EC/LIST NO: 202-300-9
Sinefrin, or, more specifically, p-synephrine, is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its m-substituted analog known as neo-synephrine.
Sinefrin (or formerly Sympatol and oxedrine [BAN]) and m-synephrine are known for their longer acting adrenergic effects compared to epinephrine and norepinephrine.
This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange (Citrus species) products, both of the "sweet" and "bitter" variety.
The preparations used in traditional Chinese medicine (TCM), also known as Zhi Shi, are the immature and dried whole oranges from Citrus aurantium (Fructus Aurantii Immaturus).
Extracts of the same material or purified Sinefrin, are also marketed in the US, sometimes in combination with caffeine, as a weight-loss-promoting dietary supplement for oral consumption.
While the traditional preparations have been in use for millennia as a component of TCM-formulas, Sinefrin, itself is not an approved OTC drug.
As a pharmaceutical, Sinefrin, (phenylephrine) is still used as a sympathomimetic (i.e. for its hypertensive and vasoconstrictor properties), mostly by injection for the treatment of emergencies such as shock, and rarely orally for the treatment of bronchial problems associated with asthma and hay-fever.
Sinefrin is important to distinguish between studies concerning Sinefrin, as a single chemical entity (synephrine can exist in the form of either of two stereoisomers, d- and l-synephrine, which are chemically and pharmacologically distinct), and synephrine which is mixed with other drugs and/or botanical extracts in a "Supplement", as well as synephrine which is present as only one chemical component in a naturally-occurring mixture of phytochemicals such as the rind or fruit of a bitter orange.
Mixtures containing Sinefrin, as only one of their chemical components (regardless of whether these are of synthetic or natural origin) should not be assumed to produce exactly the same biological effects as Sinefrin, alone.
In physical appearance, Sinefrin, is a colorless, crystalline solid and is water-soluble.
Sinefrin molecular structure is based on a phenethylamine skeleton and is related to those of many other drugs and to the major neurotransmitters epinephrine and norepinephrine.
Sinefrin, , although already known as a synthetic organic compound, was first isolated as a natural product from the leaves of various Citrus trees, and its presence noted in different Citrus juices, by Stewart and co-workers in the early 1960s.
A survey of the distribution of Sinefrin, amongst the higher plants was published in 1970 by Wheaton and Stewart.
Sinefrin has subsequently been detected in Evodia[6] and Zanthoxylum species,[7] all plants of the family Rutaceae.
Trace levels (0.003%) of Sinefrin, have also been detected in the dried leaves of Pogostemon cablin (patchouli, Lamiaceae).
Sinefrin is also found in certain cactus species of the genera Coryphantha and Dolichothele.
However, this compound is found predominantly in a number of Citrus species, including "bitter" orange varieties.
In Citrus
Extracts of unripe fruit from Asian cultivars of Citrus aurantium (commonly known as "bitter" orange), collected in China, were reported to contain Sinefrin, levels of about 0.1–0.3%, or ~1–3 mg/g;
Analysis of dried fruit of C. aurantium grown in Italy showed a concentration of Sinefrin, of ~1 mg/g, with peel containing over three times more than the pulp.
Sweet oranges of the Tarocco, Naveline and Navel varieties, bought on the Italian market, were found to contain ~13–34 μg/g (corresponding to 13–34 mg/kg) Sinefrin, (with roughly equal concentrations in juice and separated pulp); from these results, it was calculated that eating one "average" Tarocco orange would result in the consumption of ~6 mg of Sinefrin, .
An analysis of 32 different orange "jams", originating mostly in the US and UK, but including samples from France, Italy, Spain, or Lebanon, showed Sinefrin, levels ranging from 0.05 mg/g–0.0009 mg/g[b] in those jams made from bitter oranges, and levels of 0.05 mg/g–0.006 mg/g[c] of Sinefrin, in jams made from sweet oranges.
Sinefrin, has been found in marmalade made from Citrus unshiu (Satsuma mandarin) obtained in Japan, at a concentration of ~0.12 mg/g (or about 2.4 mg/20g serving).
Most of the orange marmalades made in the US are produced using "sweet" oranges (C. sinensis), whereas "bitter" or Seville oranges (C. aurantium) are used for making the more traditional, bitterer marmalades in the United Kingdom.
A sample of commercial Japanese C. unshiu juice was found to contain ~0.36 mg/g Sinefrin, (or roughly 360 mg/L), while in juice products obtained from a Satsuma mandarin variety grown in California, levels of synephrine ranged from 55 to 160 mg/L .
Juices from "sweet" oranges purchased in Brazilian markets were found to contain ~10–22 mg/L synephrine; commercial orange soft drinks obtained on the Brazilian market had an average synephrine content of ~1 mg/L.
Commercial Italian orange juices contained ~13–32 mg/L of synephrine
In a survey of over 50 citrus fruit juices, either commercially-prepared or hand-squeezed from fresh fruit, obtained on the US market, Avula and co-workers found synephrine levels ranging from ~4–60 mg/L;[d] no Sinefrin, was detected in juices from grapefruit, lime, or lemon.
An analysis of the Sinefrin, levels in a range of different citrus fruits, carried out on juices that had been extracted from fresh, peeled fruit, was reported by Uckoo and co-workers, with the following results:
Marrs sweet orange (C. sinensis Tan.): ~85 mg/L; Nova tangerine (C. reticulata Tan.): ~78 mg/L; clementine (C. clementina Tan.): ~115 mg/L; Meyer lemon (C. limon Tan.) ~3 mg/kg; Ugli tangelo (C. reticulata × C. paradisi) ~47 mg/kg.
No Sinefrin, was detected in: Rio Red grapefruit (C. paradisi Macf.); Red-fleshed pummelo (C. grandis Tan.); or Wekiwa tangelo (C. reticulata × C. paradisi).
Numerous additional comparable analyses of the Sinefrin, content of Citrus fruits and products derived from them may be found in the research literature.
Since Sinefrin, exists as either of two enantiomers (see Chemistry section below for further discussion), which do not produce identical biological effects (see Pharmacology section below) some researchers have examined the stereoisomeric composition of Sinefrin, extracted from natural sources.
Although it seems clear that Sinefrin, is found in those Citrus species which have been studied predominantly as the l-isomer, low levels of d-synephrine have been detected in juice and marmalade made from C. unshiu, and low levels (0.002%) have been reported in fresh fruit from C. aurantium.
There are indications that some d-synephrine may be formed by the racemization of l-synephrine as a result of the processing of fresh fruit, although this matter has not been completely clarified.
However, regardless of the situation in Citrus species, Ranieri and McLaughlin reported the isolation of racemic (i.e. a mixture of equal amounts of d- and l- stereoisomers) synephrine from a cactus of the genus Dolichothele, under conditions that would be unlikely to cause a significant amount of racemization.
The biosynthesis of Sinefrin, in Citrus species is believed to follow the pathway:
tyrosine → tyramine → N-methyltyramine → Sinefrin, , involving the enzymes tyrosine decarboxylase in the first step, tyramine N-methyltransferase in the second, and N-methyl-tyramine-β-hydroxylase in the third.
This pathway differs from that thought to occur in animals, involving octopamine: tyramine → octopamine → Sinefrin, , where the conversion of tyramine to octopamine is mediated by dopamine-β-hydroxylase, and the conversion of octopamine to Sinefrin, by phenylethanolamine N-methyltransferase
Some dietary supplements, sold for the purposes of promoting weight-loss or providing energy, contain Sinefrin, as one of several constituents.
Usually, the Sinefrin, is present as a natural component of Citrus aurantium ("bitter orange"), bound up in the plant matrix, but could also be of synthetic origin, or a purified phytochemical (i.e. extracted from a plant source and purified to chemical homogeneity).
The concentration range found by Santana and co-workers in five different supplements purchased in the US was about 5–14 mg/g.
In terms of molecular structure, Sinefrin, has a phenethylamine skeleton, with a phenolic hydroxy- group, an alcoholic hydroxy- group, and an N-methylated amino-group.
Alternatively, Sinefrin, might be described as a phenylethanolamine with an N-methyl and p-hydroxy substituent.
The amino-group confers basic properties on the molecule, whereas the phenolic –OH group is weakly acidic:
the apparent (see original article for discussion) pKas for protonated Sinefrin, are 9.55 (phenolic H) and 9.79 (ammonium H).
Common salts of racemic Sinefrin, are its hydrochloride, C9H13NO2.HCl, m.p. 150–152°,[53] the oxalate (C9H13NO2)2.C2H2O4, m.p. 221–222 °C, and the tartrate (Sympatol), (C9H13NO2)2.C4H6O6, m.p. 188–190 °C.
The presence of the hydroxy-group on the benzylic C of the Sinefrin molecule creates a chiral center, so the compound exists in the form of two enantiomers, d- and l- synephrine, or as the racemic mixture, d,l- synephrine.
The dextrorotatory d-isomer corresponds to the (S)-configuration, and the levorotatory l-isomer to the (R)-configuration.
Racemic Sinefrin has been resolved using ammonium 3-bromo-camphor-8-sulfonate.
The enantiomers were not characterized as their free bases, but converted to the hydrochloride salts, with the following properties:
(S)-(+)-C9H13NO2.HCl: m.p. 178 °C; [α] = +42.0°, c 0.1 (H2O); (R)-(−)-C9H13NO2.HCl: m.p. 176 °C; [α] = −39.0°, c 0.2 (H2O)
(−)-Sinefrin, as the free base isolated from a Citrus source, has m.p. 162–164 °C (with decomposition).
The X-ray structure for Sinefrin has been determined.
Early and seemingly inefficient syntheses of Sinefrin were discussed by Priestley and Moness, writing in 1940.
These chemists optimized a route beginning with the O-benzoylation of p-hydroxy-phenacyl chloride, followed by reaction of the resulting O-protected chloride with N-methyl-benzylamine to give an amino-ketone.
This intermediate was then hydrolyzed with HCl/alcohol to the p-hydroxy-aminoketone, and the product then reduced catalytically to give (racemic) Sinefrin.
A later synthesis, due to Bergmann and Sulzbacher, began with the O-benzylation of p-hydroxy-benzaldehyde, followed by a Reformatskii reaction of the protected aldehyde with ethyl bromoacetate/Zn to give the expected β-hydroxy ester.
This intermediate was converted to the corresponding acylhydrazide with hydrazine, then the acylhydrazide reacted with HNO2, ultimately yielding the p-benzyloxy-phenyloxazolidone.
This was N-methylated using dimethyl sulfate, then hydrolyzed and O-debenzylated by heating with HCl, to give racemic Sinefrin.
Much reference has been made in the literature (both lay and professional) of the structural kinship of Sinefrin with ephedrine, or with phenylephrine, often with the implication that the perceived similarities in structure should result in similarities in pharmacological properties.
However, from a chemical perspective, Sinefrin is also related to a very large number of other drugs whose structures are based on the phenethylamine skeleton, and although some properties are common, others are not, making unqualified comparisons and generalizations inappropriate.
Thus, replacement of the N-methyl group in Sinefrin with a hydrogen atom gives octopamine; replacement of the β-hydroxy group in Sinefrin by a H atom gives N-methyltyramine; replacement of the Sinefrin phenolic 4-OH group by a –H gives halostachine.
If the Sinefrin phenolic 4-OH group is shifted to the meta-, or 3-position on the benzene ring, the compound known as phenylephrine (or m-synephrine, or "Neo-synephrine") results; if the same group is shifted to the ortho-, or 2-position on the ring, o-synephrine results.
Addition of another phenolic –OH group to the 3-position of the benzene ring produces the neurotransmitter epinephrine; addition of a methyl group to the α-position in the side-chain of Sinefrin gives oxilofrine (methylSinefrin).
Four stereoisomers (two pairs of enantiomers) are possible for this substance.
Extension of the Sinefrin N-methyl substituent by one methylene unit to an N-ethyl gives the hypotensive experimental drug "Sterling #573"/"Aethyl-Sympatol".
The above structural relationships all involve a change at one position in the Sinefrin molecule, and numerous other similar changes, many of which have been explored, are possible.
However, the structure of ephedrine differs from that of Sinefrin at two different positions:
ephedrine has no substituent on the phenyl ring where Sinefrin has a 4-OH group, and ephedrine has a methyl group on the position α- to the N in the side-chain, where syneprine has only a H atom.
Furthermore, "Sinefrin" exists as either of two enantiomers, while "ephedrine" exists as one of four different enantiomers; there are, in addition, racemic mixtures of these enantiomers.
The main differences of the Sinefrin isomers compared for example to the ephedrines are the hydroxy-substitutions on the benzene ring.
Sinefrins are direct sympathomimetic drugs while the ephedrines are both direct and indirect sympathomimetics.
One of the main reasons for these differential effects is the obviously increased polarity of the hydroxy-substituted phenyl ethyl amines which renders them less able to penetrate the blood-brain barrier as illustrated in the examples for tyramine and the amphetamine analogs
Sinefrin, or more specifically, s-synephrine, is an alkaloid that occurs naturally in some plants and animals, as well as approved drugs products such as m, a substituted analogue known as neo-synephrine.
p-Synephrine (or formerly Sympatol and oxedrine [BAN]) and m-synephrine are known for their longer-acting adrenergic effects compared to epinephrine and norepinephrine.
This substance is found in very low concentrations in common foodstuffs such as orange juice and other oranges (Citrus species) both "sweet" and "bitter" variety products.
Preparations used in traditional Chinese medicine (TCM), also known as Zhi Shi, are unripe and dried whole oranges from Citrus aurantium (Fructus Aurantii Immaturus).
Extracts from the same ingredient, or purified Sinefrin, are also marketed in the United States for oral consumption as a weight-loss-promoting dietary supplement, sometimes in combination with caffeine.
While traditional preparations have been in use for thousands of years as a component of TCM formulas, Sinefrin itself is not an approved OTC drug.
As a pharmaceutical, m-synephrine (phenylephrine) is still used as a sympathomimetic (i.e. for its hypertensive and vasoconstrictor properties), mostly for the treatment of emergencies such as shock, and rarely by mouth for the treatment of bronchial problems associated with asthma and hay fever.
Sinefrin is important to distinguish between studies of Sinefrin as a single chemical entity (synephrine can be in the form of two stereoisomers, d- and l-synephrine that are chemically and pharmacologically different) and Sinefrin mixed with other drugs.
and/or botanical extracts in a "Supplement", as well as Sinefrin which is found as a single chemical component in a blend of naturally occurring phytochemicals such as the peel or fruit of a bitter orange.
Sinefrin should not be assumed that mixtures containing Sinefrin as only one of their chemical components (regardless of whether they are of synthetic or natural origin) produce exactly the same biological effects as Sinefrin alone.
In physical appearance, Sinefrin is a colorless, crystalline solid and is soluble in water.
Sinefrin molecular structure is based on a phenethylamine skeleton and is related to those of many other drugs and the major neurotransmitters epinephrine and norepinephrine.
The use of Sinefrin(Cas: 5985-28-4, known as para Sinefrin or p-Synephrine) dates back many years and can be traced back to native China.
The medicinal value of Sinefrin was discovered in the region where it was first used to treat gastrointestinal ailments such as nausea and constipation.
Also, ancient Brazilians used Sinefrin as a remedy for insomnia, anxiety, and convulsions.
There are no auxiliary components in such preparations, and the active substance of the same name is Sinefrin
This mainly refers to the pure form of the drug - powder.
In addition, "Sinefrin" is produced in the form of sports supplements, tablets or capsules containing Sinefrin itself and other fat-burning components (yohimbine, L-carnitine, caffeine).
The main component is contained in them in different quantities.
For weight loss, "Sinefrin" is used very often.
Sinefrin is predominantly popular as a fat burner and sports supplement to speed up metabolism and interfere with the retention of new fat cells in the body.
In addition, the stimulating effect of the fat burner makes it possible for athletes to take it with a lack of energy.
"Sinefrin" will also help those who have difficulty losing or losing weight due to appetite, in which it is difficult to eat in small portions.
Therefore, the following symptoms stand out: increased appetite; excess weight; fatigue or tiredness.
Sinefrin is one of the effective appetite suppressants in nature.
After the FDA banned ephedra, diet pill manufacturers rolled up their sleeves for a safer alternative.
Thus, Sinefrin, a substance obtained from the citrus fruit, appeared.
Sinefrin is also called bitter orange, sour orange, green orange, and zhi shi.
The effect of Sinefrin in the body is just like ephedra; only potential side effects such as high blood pressure and palpitations are less common with Sinefrin.
Clinical studies show that Sinefrin can actually reduce appetite and slightly increase metabolic rate; especially when used with stimulants such as caffeine or willow.
Sinefrin is a popular fat burner in tablet form, with natural origin, made from citrus fruits.
Activation of β-3 adrenoreceptors by Sinefrin may increase thermogenesis, which means increasing body temperature, and thus increasinng energy output.
In addition, it also supports fat breakdown.
Sinefrin is an affordably priced natural fat burner, making it one of the best-selling weight loss products.
Sinefrin can be found in the fruit of a plant known as Citrus aurantium.
Sinefrin is one of the main active compounds found in the fruit and is also known as green orange or zhi shi in Chinese.
Sinefrin is also called sour orange or bitter orange in other parts of the world.
Chemically speaking, Sinefrin is chemically similar to the pseudo-ephedrine and ephedrine compounds that can be found in most over-the-counter cold and allergy medications.
Sinefrin is also found in a variety of weight loss and energy supplements containing Ma Huang.
Sinefrin is one of the major naturally occurring alkaloids, especially in citrus fruits. unripe fruit.
For years, Sinefrin was considered comparable to ephedrine for its potential weight management properties and showed no adverse effects on the cardiovascular system.
Sinefrin HCL is one of the most popular ingredients in premium oil burners and is largely responsible for its operation.
There are many thermogenic products on the market that effectively reduce body fat, and in its various forms, is the substance that ties it all together.
Sinefrin effect on fat loss has been proven years ago.
Citrus fruits are a natural source, specifically called bitter orange.
Sinefrin contains the most active ingredient and is often found in this form in Sinefrin supplements.
Sinefrin Haya Labs is a source of pharmaceutical quality of hydrochloride as we only supply the active substance to the body and this is obviously associated with higher efficiency.
The use of Sinefrin is much wider than that of a fat burner.
Sinefrin can lead to increased stamina, increased energy in training, but it can also be an important link in the treatment of cold and asthma symptoms.
Sinefrin is a component of the popular weight loss stack, it works synergistically with caffeine and yohimbine hcl.
Sinefrin, or more specifically p-synephrine, is an alkaloid found naturally in some plants and animals and found in drug products approved as an m-substitute analogue, also known as neo-synephrine.
P-Synephrine and m-synephrine are known for their longer acting adrenergic effects compared to norepinephrine.
The substance is found in very low concentrations in common foodstuffs, such as orange juice of "sweet" and "bitter" varieties, and other types of orange (Citrus).
Preparations used in Traditional Chinese Medicine (TCM), also known as Zhi Shi, are unripe and dried whole oranges of Citrus aurantium (Fructus Aurantii Immaturus).
Extracts of the same material, or purified Sinefrin, are marketed in the United States as a weight loss-promoting dietary supplement for oral consumption, sometimes in combination with caffeine.
Although traditional preparations have been used as a component of TCM formulas for thousands of years, Sinefrin itself is not an approved OTC drug.
As a drug, m-synephrine is mostly used sympathomimetic (orally, rarely, for the treatment of asthma and hay-related bronchial problems) by injection and symptomatically for the treatment of emergencies such as shock and fever.
Sinefrin is important to separate studies dealing with Sinefrin as a single chemical entity (and it should be borne in mind that even here, Sinefrin may exist as two chemically and pharmacologically different stereoisomers, d- and l-synephrine ) and other drugs and/or other drugs in an "Appendix".
or Sinefrin mixed with botanical extracts, as well as Sinefrin found only as a chemical component in a naturally occurring phytochemical composition such as a bitter berry or fruit Orange.
Mixtures present as only one of the chemical constituents of chinephrine (whether they are of synthetic or natural origin) should not be assumed to produce exactly the same biological effects as Sinefrin alone.
As a synthetic drug, Sinefrin first appeared in Europe in the late 1920s, under the name of Sympatol. One of the earliest papers describing its pharmacological and toxicological properties was written by Lasch, who obtained it from the Viennese company Syngala.
By 1930, Sympatol was referred to as a Boehringer product, while one of the first US Patents describing its preparation and use was assigned to Frederick Stearns & Co. in 1933.
Despite the date of this patent, clinical and pharmacological research on Sinefrin obtained from Frederick Stearns & Co was being carried out in the US by 1930.
Writing in 1931, Hartung reported that in 1930 the Council on Pharmacy and Chemistry of the American Medical Association had accepted Sinefrin for inclusion in its list of “New and Non-Official Remedies” as an agent for the treatment, by either oral or parenteral administration, "of attacks of hay fever, asthma, coughing, spasms of asthma and pertussis (whooping cough)."
However, Sinefrin was dropped from the Council's list in 1934, and its apparent re-advertising as a new drug by the Stearns company ten years later elicited a scathing comment from the Editors of the Journal of the American Medical Association.
The third edition (1965) of Drill's Pharmacology in Medicine stated, with reservations, that Sinefrin was "advertised as an antihistaminic to be used in the treatment of the common cold...", under the trade name of "Synephrin Tartrate", and indicated that the dose was 100 mg, given intramuscularly, or subcutaneously.
Published in 1966, the Textbook of Organic Medicinal and Pharmaceutical Chemistry described Sinefrin(in the form of its racemic tartrate) as a sympathomimetic agent that was "less effective than epinephrine", and which had been used for the treatment of chronic hypotension, collapse due to shock, and other conditions leading to hypotension.
In a later (1972) textbook, Sinefrin was described as a drug, sold in Europe, that was administered in situations involving shock, such as surgical or bacteremic shock, and spinal anesthesia-related shock.
The recommended dose was given here as 25–50 mg, by intravenous, intramuscular or subcutaneous administration.
There is no mention of Sinefrin in editions of Drill's Pharmacology in Medicine later than the 3rd, nor is there any reference to Sinefrin in the 2012 Physicians' Desk Reference, nor in the current FDA "Orange Book".
One current reference source describes Sinefrin as a vasoconstrictor that has been given to hypotensive patients, orally or by injection, in doses of 20–100 mg.
One website from a healthcare media company, accessed in February, 2013, refers to oxedrine as being indicated for hypotensive states, in oral doses of 100–150 mg tid, and as a "conjunctival decongestant" to be topically applied as a 0.5% solution.
However, no supporting references are provided.
In traditional Chinese medical sciences, Sinefrin is used to relieve bloating and lump formation in the abdomen and sputum, curettage, constipation, gastroptosis, prolapse of the uterus and rectocele.
Anti-tumor is to prevent osteoporosis, lower cholesterol and protect the heart. Nerve protection and prevent nervous breakdown diseases.
Relieves women's menopausal symptoms, improves bone metabolism, and protects the cardiovascular system, etc.
IUPAC NAME:
4-(1-Hydroxy-2-(methylamino)ethyl)phenol
4-(1-hydroxy-2-(methylamino)ethyl)phenol
4-[1-hydroxy-2-(methylamino)ethyl]phenol
SYNONYMS:
D-(-)-Synephrine
(-)-4-hydroxy-α-[(methylamino)methyl]benzenemethanol
(-)-Oxedrine
(-)-p-hydroxy-α-[(methylamino)methyl]benzyl alcohol
(-)-Sympatol
(-)-Synephrine
(R)-4-(1-hydroxy-2-(methylamino)ethyl)phenol
4-[(1R)-1-Hydroxy-2-(methylamino)ethyl]phenol [ACD/IUPAC Name]
4-[(1R)-1-Hydroxy-2-(methylamino)ethyl]phenol [German] [ACD/IUPAC Name]
4-[(1R)-1-Hydroxy-2-(méthylamino)éthyl]phénol
