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Norepinephrine bitartrate

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(+-)-Norepinephrine bitartrate.png
2D chemical structure of 3414-63-9

Norepinephrine bitartrate

Arterenol bitartrate
RN: 3414-63-9

FREE FORM 138-65-8

UNIIIFY5PE3ZRW

R FORM CAS Number108341-18-0,

  • 1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (salt), monohydrate
  • 1,2-Benzenediol, 4-[(1R)-2-amino-1-hydroxyethyl]-, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (salt), monohydrate (9CI)
  • Arterenol, tartrate, monohydrate (6CI)
  • L-Noradrenaline bitartrate monohydrate
  • Levarterenol bitartrate monohydrate

WeightAverage: 337.281
Chemical FormulaC12H19NO10

(+-)-Arterenol bitartrate

(+-)-Noradrenaline bitartrate

(+-)-Norepinephrine bitartrate

(2R,3R)-2,3-dihydroxybutanedioic acid 4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol hydrate

ORD +41.3 °, water, 4% ; Wavlen: 589.3 nm; Temp: 25 °C, AND MP 163-165 °C, GB 747768 1956 NorepinephrineCAS Registry Number: 51-41-2CAS Name: 4-[(1R)-2-Amino-1-hydroxyethyl]-1,2-benzenediolAdditional Names: (-)-a-(aminomethyl)-3,4-dihydroxybenzyl alcohol; l-3,4-dihydroxyphenylethanolamine; noradrenaline; levarterenolTrademarks: Adrenor; Levophed (Winthrop)Molecular Formula: C8H11NO3Molecular Weight: 169.18Percent Composition: C 56.79%, H 6.55%, N 8.28%, O 28.37%Literature References: Demethylated precursor of epinephrine, q.v. Occurs in animals and man, and is a sympathomimetic hormone of both adrenal origin and adrenergic orthosympathetic postganglionic origin in man. Physiologic review: Malmejac, Physiol. Rev.44, 186 (1964). It has also been found in plants, e.g., Portulaca olerocea L., Portulacaceae: Fing et al.,Nature191, 1108 (1961). Synthesis of dl-form: Payne, Ind. Chem.37, 523 (1961). Historic review of synthesis: Loewe, Arzneim.-Forsch.4, 583 (1954). Resolution of dl-form: Tullar, J. Am. Chem. Soc.70, 2067 (1948); idem,US2774789 (1956 to Sterling Drug). Configuration: Pratesi et al.,J. Chem. Soc.1959, 4062. Comprehensive description: C. F. Schwender, Anal. Profiles Drug Subs.1, 149-173 (1972); T. D. Wilson, ibid.11, 555-586 (1982).Properties: Microcrystals, dec 216.5-218°. [a]D25 -37.3° (c = 5 in water with 1 equiv HCl).Optical Rotation: [a]D25 -37.3° (c = 5 in water with 1 equiv HCl) 
Derivative Type: HydrochlorideCAS Registry Number: 329-56-6Trademarks: Arterenol (HMR)Molecular Formula: C8H11NO3.HClMolecular Weight: 205.64Percent Composition: C 46.73%, H 5.88%, N 6.81%, O 23.34%, Cl 17.24%Properties: Crystals, mp 145.2-146.4°. [a]D25 -40° (c = 6). Freely sol in water. Solns slowly oxidize under the influence of light and oxygen in a manner comparable to epinephrine hydrochloride.Melting point: mp 145.2-146.4°Optical Rotation: [a]D25 -40° (c = 6) 
Derivative Type:d-BitartrateCAS Registry Number: 69815-49-2Additional Names: Levarterenol bitartrateTrademarks: Aktamin; BinodrenalMolecular Formula: C8H11NO3.C4H6O6Molecular Weight: 319.26Percent Composition: C 45.14%, H 5.37%, N 4.39%, O 45.10%Properties: Obtained as the monohydrate, crystals, mp 102-104°. [a]D25 -10.7° (c = 1.6 in H2O). When anhydr, mp 158-159° (some decompn). Freely sol in water.Melting point: mp 102-104°; mp 158-159° (some decompn)Optical Rotation: [a]D25 -10.7° (c = 1.6 in H2O) 
Derivative Type:dl-FormProperties: Crystals, dec 191°. Sparingly sol in water; very slightly sol in alc, ether; readily sol in dilute acids, caustic. 
Therap-Cat: Adrenergic (vasopressor); antihypotensive.Therap-Cat-Vet: Sympathomimetic; vasopressor in shock.Keywords: a-Adrenergic Agonist; Antihypotensive.

Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic.

Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a sympathomimetic amine which differs from epinephrine by the absence of a methyl group on the nitrogen atom.

Norepinephrine Bitartrate is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate and has the following structural formula:

Levophed™ (norepinephrine bitartrate) Structural Formula Illustration

LEVOPHED is supplied in sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion following dilution. Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Each mL contains the equivalent of 1 mg base of norepinephrine, sodium chloride for isotonicity, and not more than 2 mg of sodium metabisulfite as an antioxidant. It has a pH of 3 to 4.5. The air in the ampuls has been displaced by nitrogen gas.

Norepinephrine, also known as noradrenaline, is a medication used to treat people with very low blood pressure.[2] It is the typical medication used in sepsis if low blood pressure does not improve following intravenous fluids.[3] It is the same molecule as the hormone and neurotransmitter norepinephrine.[2] It is given by slow injection into a vein.[2]

Common side effects include headache, slow heart rate, and anxiety.[2] Other side effects include an irregular heartbeat.[2] If it leaks out of the vein at the site it is being given, norepinephrine can result in limb ischemia.[2] If leakage occurs the use of phentolamine in the area affected may improve outcomes.[2] Norepinephrine works by binding and activating alpha adrenergic receptors.[2]

Norepinephrine was discovered in 1946 and was approved for medical use in the United States in 1950.[2][4] It is available as a generic medication.[2]

Medical uses

Norepinephrine is used mainly as a sympathomimetic drug to treat people in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment.[5][6]

Mechanism of action

It stimulates α1 and α2 adrenergic receptors to cause blood vessel contraction, thus increases peripheral vascular resistance and resulted in increased blood pressure. This effect also reduces the blood supply to gastrointestinal tract and kidneys. Norepinephrine acts on beta-1 adrenergic receptors, causing increase in heart rate and cardiac output.[7] However, the elevation in heart rate is only transient, as baroreceptor response to the rise in blood pressure as well as enhanced vagal tone ultimately result in a sustained decrease in heart rate.[8] Norepinephrine acts more on alpha receptors than the beta receptors.[9]

Names

Norepinephrine is the INN while noradrenaline is the BAN.

SYN

Chemical Synthesis

Norepinephrine, L-1-(3,4-dihydroxyphenyl)-2-aminoethanol (11.1.4), is synthesized by two methods starting from 3,4-dihydroxybenzaldehyde. According to the first method, the indicated aldehyde is transformed into the cyanohydrin (11.1.3) by reaction with hydrogen cyanide, which is then reduced into norepinephrine (11.1.5).

The second method consists of the condensation of diacetate of the same aldehyde with nitromethane, which forms (3,4-diacetoxyphenyl)-2-nitroethanol (11.1.5). Then the nitro group is reduced and the product (11.1.6) is hydrolyzed into the desired norepinephrine (11.1.4) [4,9,13,14].

Purification Methods

Recrystallise adrenor from EtOH and store it in the dark under N2. [pKa, Lewis Brit J Pharmacol Chemother 9 488 1954, UV: Bergstr.m et al. Acta Physiol Scand 20 101 1950, Fluorescence: Bowman et al. Science NY 122 32 1955, Tullar J Am Chem Soc 70 2067 1948.] The L-tartrate salt monohydrate has m 102-104.5o, [] D -11o (c 1.6, H2O), after recrystallisation from H2O or EtOH. [Beilstein 13 III 2382.]

PATENT

https://patents.google.com/patent/WO2013008247A1/en4-[(lR)-2-amino-l-hydroxyethyl]benzene-l,2-diol, commonly known as (R)-(-)- norepinephrine or noradrenaline is a catecholamine with multiple roles including as a hormone and a neurotransmitter. As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine also has a neurotransmitter role when released diffusely in the brain as an antiinflammatory agent.When norepinephrine acts as a drug it increases blood pressure by increasing vascular tone through a-adrenergic receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called reflex bradycardia.(R)-(-)-Norepinephrine has a following structure:

Figure imgf000002_0001

(R)-(-)-Norepinephrine was first time disclosed in the US patent US2774789, where it was obtained by resolution of dl-norepinephrine, with optically active acids such as d- tartaric acid, 1-malic acid or N-benzoyl-l-threonine. The patent does not disclose the preparation of dl-norepinephrine. The patent GB747768 describes reduction of amino ketones where 3,4-dihydroxy-a- aminoacetophenone hydrochloride was converted into its d-tartrate salt; followed by reduction of the d-tartrate salt. This process leads to formation of excessive amount of d- adrenaline d-tartrate (which is a bi-product) as it crystallized first; whereas the desired 1- adrenaline d-tartrate crystallizes after 2 days and in smaller yield. Also the patent does not disclose the source of 3,4-dihydroxy-a-aminoacetophenone hydrochloride.It has been unsuccessfully tried to treat dihydroxy-a-chloroacetophenone with hexamethylenetetramine (commonly known as hexamine) and to treat the reaction product with an acid to obtain arterenone (see Mannich, Hahn B., Berichte der deutschen chemischen Gesellschaft, volume 44, issue 2, Pages 1542 – 1552 (1911)). Mannich found that the treatment of this and similar halogen ketones with hexamine did not produce an addition compound but resulted in splitting of halogen acid which made the process impossible. Mannich also found that an addition compound of the halogen ketone and hexamine is formed only when the two phenolic hydroxyl groups are closed i.e. protected by acylation or etherification. Hence according to Mannich, the reaction is not at all possible for the compounds containing two unprotected phenolic hydroxyl groups. The US patent US 1680055 discloses the preparation of monohydroxy-a-substituted- aminoacetophenones either by reacting monohydroxy-a-bromoacetophenones with a substituted amine or by reacting protected monohydroxy-a-bromoacetophenones with a substituted amine followed by deprotection. The patent does not disclose the preparation of dihydroxy-a-aminoacetophenones (where amino group is unsubstituted).It is disclosed in the US patent US2786871 that when chloroaceto pyrocatechol is treated with ammonia, arterenone is obtained in 50% yield. However when the reaction is carried out in basic medium, darkening of the reaction mass takes place which results in coloured product. The patent also discloses preparation of amino-methyl-(monohydroxyphenyl)- ketones by reacting halogen ketone with hexamine. It is also disclosed in the patent that the process is applicable only to the halogenomethyl-monohydroxyphenyl-ketones.Following are some of the methods for preparation of 3,4-dihydroxy-a- aminoacetophenone, reported in the literature. J. Am. Pharm. Association (1946) 35, 306 – 309 discloses preparation of 3,4-dihydroxy- a-aminoacetophenone by reacting 3,4-dihydroxy-a-chloroacetophenone with dibenzyl amine followed by hydrogenation of resulting dibenzylamino ketone. The main disadvantage of this reaction is formation of derivatives of dibenzyl amines, which remain in the final product in the form of impurities.Acta Chimica Academiae Scientiarum Hungaricae (1951), 1, 395-402, discloses preparation of 3,4-dihydroxy-a-aminoacetophenone from 3,4-dihydroxyphenyloxo acetaldehyde and benzyl amine followed by reduction of benzylamino ketone intermediate. The main disadvantage of this method is that the starting acetaldehyde derivative is very expensive and not easily available.It is disclosed in Recueil des Travaux Chimiques des Pays-Bas et de la Belgique (1952), 71, 933-44, that 3,4-dihydroxy-a-aminoacetophenone hydrochloride is formed by demethylation of 3,4-dimethoxy-a-aminoacetophenone hydrochloride using 48% HBr. The reaction results in less than 10% yield of the aminoacetophenone.Monatshefte fuer Chemie (1953), 84 1021-32, discloses preparation of 3,4-dihydroxy-a- aminoacetophenone by reacting 3,4-dihydroxy-a-chloroacetophenone with sodium azide followed by hydrogenation of azide intermediate using 4% palladium on carbon as a catalyst. In the hydrogenation step, 1.6 gm of azide intermediate requires 1.4 gm of catalyst, which is not economical and industrially feasible.

Preparation of 3,4-dihydroxy-a-aminoacetophenones hydrochloride is disclosed in J. Am. Chem. Soc, 1955, volume 77, issue 10, pages 2896 – 2897. The following scheme is disclosed in the article:

Figure imgf000004_0001
Figure imgf000004_0002

It is clear from the above scheme that the process requires additional steps of protection and deprotection of hydroxyl and amino groups, and use of potassium phthalimide requires anhydrous reaction conditions. Therefore the process is time consuming and not economical.Chinese patent CN101798271A describes reduction of 3,4-dihydroxy-a- aminoacetophenone hydrochloride in water as solvent followed by neutralization with aqueous ammonia. Since dl-norepinephrine has partial solubility in aqueous basic medium result in to loss of product. Also it is necessary to maintain low volume of solvent throughout the process for better yields making the process stringent.European patent EP1930313 discloses preparation of a-amino ketones. The preparation is carried out by reacting an organic sulfide in a polar solvent with a compound containing a leaving group attached to a primary or secondary carbon atom to form a sulfonium salt, which is reacted with a ketone in presence of a base and a polar solvent. Oxiranes obtained are further converted into the corresponding aminoketone, by aminolysis followed by selective oxidation. The following scheme is disclosed in the patent.

Figure imgf000005_0001

It is clear from the above scheme that the process requires many steps and hence is time consuming. The patent does not exemplify the synthesis of dihydroxy-a- aminoacetophenones.Thus, the search for a suitable manufacturing process for (R)-norepinephrine intermediates remains undoubtedly of interest. We were surprised to find that hardly any literature discloses the process for preparation of dihydroxy-a-aminoacetophenones acid addition salts. We have found that the reaction of dihydroxy-a-haloacetophenone with hexamine is feasible and results in high yield of product although both the hydroxyl groups on the phenyl ring of acetophenone are unprotected. Object of the invention:It is therefore an object of the invention is to overcome or ameliorate at least one disadvantage of the prior art or to provide a useful alternative.Another object of the invention is to provide a novel, safe, efficient, concise, ecological, high yielding, industrially feasible and simpler process for preparation of (R)-(-)- norepinephrine intermediates.Another object of the invention is to provide a process for synthesis of 3,4-dihydroxy-a- aminoacetophenone salt, which is feasible without protecting both the hydroxyl group on the phenyl ring of acetophenone.Yet another object of the invention is to provide an improved process for hydrogenation of 3,4-dihydroxy-a-aminoacetophenone salt to prepare (dl)-norepinephrine salt.Summary of the invention:In accordance with the above objectives, the present invention provides a process for preparation of (dl)-norepinephrine intermediate of formula (III) comprising reacting 3,4- dihydroxy-a-haloacetophenone of formula (I) with hexamine to provide a quaternary ammonium salt of formula (II); followed by hydrolyzing the quaternary ammonium salt of formula (II) with an acid.In a second aspect, the present invention provides a novel quaternary ammonium salt of formula (II) and its preparation.In a third aspect, the present invention provides a novel process for hydrogenation of 3,4- dihydroxy-a-aminoacetophenone acid salt to provide (dl)-norepinephrine acid addition salt.Example 1Preparation of quaternary ammonium saltA 5000 ml four neck round bottom flask with water condenser and calcium chloride tube was charged with Hexamine (210.28 gm), chloroform (1200 ml), 3,4-dihydroxy-a- chloroacetophenone (250 gm) and isopropanol (1000 ml) at room temperature. The reaction mass was gently heated at 63°C for 4 hours. The reaction was monitored by TLC. The reaction mass was cooled to room temperature and filtered to get solid. The solid was washed with acetone and dried at 50°C for 4 hours to obtain quaternary ammonium salt which was used in the next step without purification.Yield – 410 gm (93.65%)Nature – off white solidm.p. – 180 to l82°CNMR (DMSO-d6): – δ =4.51 – 4.75 (m, 8H), 5.39 (s, 6H), 6.92 (d, 1H, J= 7.5 Hz), 7.37 – 7.42 (m, 2H), 9.67 (s, br, 1H), 10.44 (s, br, 1H)Example 2Preparation of 3,4-dihydroxy-a-aminoacetophenone hydrochlorideA 2000 ml four neck round bottom flask with water condenser and calcium chloride tube was charged with the quaternary ammonium salt obtained in the example 1 (120 gm), methanol (862.5 ml) and cone, hydrochloric acid (194.4 ml). The reaction mixture was heated to 60 to 65°C and aged at same temperature for 3 to 4 hours. The reaction was monitored by TLC. The reaction mass was cooled and neutralized using base to give 3,4- dihydroxy-a-aminoacetophenone. The solid was filtered, washed with water and dried at 50°C. This base was further converted in to its hydrochloride salt with IPA-HC1 mixture. Yield – 72 gm (96.3%)Nature – off white solidHPLC – 99.7%1H NMR(CD30D) – 5 = 3.62(s, 1H), 6.80 (d, J = 8 Hz, 1H), 7.38 (d, J = 1.3 Hz, 1H), 7.63 (d, J = 8 Hz, 1H).Example 3Preparation of (dl)-norepinephrine hydrochlorideA 500 ml hydrogenation flask was charged with 3,4-dihydroxy-a-aminoacetophenone hydrochloride obtained in the example 2 (55 gm), 10% palladium on carbon (5 gm) and methanol (300 ml). The reaction mixture was heated to 45°C with hydrogen gas pressure of 4 to 5 kg m2. The reaction mixture was stirred at 45°C for 5 hours. The catalyst was removed by filtration. The filtrate was cooled to 5 to 10 °C and ammonia gas was passed through the solvent for 2 h till the pH of the solution was around 9. The solid obtained was filtered, washed with methanol and dried in air to obtain (dl)-norepinephrine. Yield – 43.5 gm (96.7%)Nature white crystalline solidHPLC 99.6%Example 4Preparation of (dl)-norepinephrine hydrochlorideA 500 ml hydrogenation flask was charged with 3,4-dihydroxy-a-aminoacetophenone hydrochloride obtained from process similar to example 2 (55 gm), 10% palladium on carbon (5 gm) and methanol (300 ml). The reaction mixture was aged at 25 °C with hydrogen gas pressure of 4 to 3 kg/m2. The reaction mixture was stirred at 25°C for 15 hours. The reaction was monitored by TLC. The catalyst was removed by filtration. The filtrate was cooled to 5 to 10 °C and ammonia solution was added to the reaction mixture till the pH of the solution around 9. The solid obtained was filtered, washed with methanol and dried in air to obtain (dl)-norepinephrine.Yield – 41.5 gm (92.2%)Nature – white crystalline solidHPLC – 99.5% 
PATENTUS-10865180https://patentscope.wipo.int/search/en/detail.jsf?docId=US283323778&_cid=P11-KMEC1N-93277-1

Norepinephrine Bitartrate (Arterenol Bitartrate) is chemically known as (−)-α-(aminomethyl)-3, 4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate is a catecholamine family that functions in the brain and body as a hormone and neurotransmitter. As a stress hormone, Norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, Norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine also has a neurotransmitter role when released diffusely in the brain as an anti-inflammatory agent.
      LEVOPHED® (l-Norepinephrine) is supplied in sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion following dilution. Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Each ml contains the equivalent of 1 mg base of Norepinephrine, sodium chloride for isotonicity, and not more than 2 mg of sodium metabisulfite as an antioxidant.
      Norepinephrine Bitartrate is (−)-α-(amino methyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate and has the following structural formula:

 (MOL) (CDX)
      (l)-Norepinephrine was first disclosed in 1947 by Sterling Drugs. U.S. Pat. No. 2,774,789 discloses the resolution of dl-Norepinephrine with optically active acids such as d-tartaric acid, 1-malic acid or N-benzoyl-l-threonine. The patent does not disclose the basic synthesis of dl-Norepinephrine.
       Journal of the American Chemical Society, Volume 70 (6), 1948 describes the resolution of dl-Norepinephrine in to d-arterenol-d-bitartrate and l-arterenol-d-bitartrate in water and aqueous methanol. Further it also describes isolation of d-arterenol and l-arterenol form above tartrate salts.
      U.S. Pat. No. 2,786,871 discloses the process for the preparation of arterenol wherein chloroacetopyrocatechol is treated with ammonia and arterenol is obtained in 50% yield.
       J. Am. Pharm. Association (1946) 35, 306-309 discloses preparation of 3,4-dihydroxyaminoacetophenone by reacting 3,4-dihydroxy-α-chloroacetophenone with dibenzyl amine, followed by hydrogenation of the resulting dibenzylamino ketone. The main disadvantage of this reaction is the formation of derivatives of dibenzyl amines, which carried over to final product in the form of impurities.
       Acta Chimica Academiae Scientiarum Hungaricae (1951), 1, 395-402 discloses preparation of 3, 4-dihydroxy-α-aminoacetophenone from 3,4-dihydroxyphenyloxo acetaldehyde and benzyl amine followed by reduction of the benzylamino ketone intermediate. The main disadvantage of this method is that the starting acetaldehyde derivative is very expensive and not easily available.
      CN101798271A describes reduction of 3,4-dihydroxy-α-aminoacetophenone hydrochloride in water as solvent followed by neutralization with aqueous ammonia. Since dl-Norepinephrine has partial solubility in aqueous basic medium, this process results in a loss of product. Also, it is necessary to maintain low volume of solvent throughout the process for better yields making the process stringent.
      WO2009004593 describes the process for the preparation of Epinephrine wherein (−) epinephrine is obtained by chiral separation of dl-epinephrine using the chiral acid such as L-tartaric acid with an optical purity of 95.24%.
      WO2013008247 discloses a process for preparation of (dl)-norepinephrine hydrochloride salt by reacting 3,4-dihydroxy-a-haloacetophenone with hexamethylenetetramine to provide hexamine salt; followed by hydrolysis and hydrogenation. However, this process fails to teach the resolution of (dl)-norepinephrine hydrochloride and preparation of l-Norepinephrine Bitartrate monohydrate.
      WO2016038422 discloses a process for the preparation of optically enriched adrenaline or adrenaline tartrate comprising the steps of: (a) reacting a mixture of (−)-adrenaline and (+)-adrenaline with L(+)-tartaric acid to form adrenaline tartrate; (b) contacting the adrenaline tartrate with less than 1 equivalent of ammonium hydroxide. However, the product achieved is with purity of only 98%.
      CN107298646 describes the process for the preparation of Norepinephrine wherein L-Norepinephrine tartrate is obtained by chiral separation of dl-Norepinephrine using the chiral acid such as L-tartaric acid. The chiral separation step using L-tartaric acid is repeated once to obtain pure Norepinephrine. However, there is no information on bitartrate salt and its optical purity.
      In light of the above, there remains a need in the art for highly pure l-Norepinephrine Bitartrate having high enantiomeric purity i.e. greater than 99.0% so as to provide enhanced therapeutic efficacy and safety when administered. Surprisingly the present inventors have found out a process for the preparation of (l)-Norepinephrine Bitartrate having enantiomeric purity greater than 99.5%, for which protection is sought.

Reference Example-1(U.S. Pat. No. 2,774,789, Example-A)

Preparation of l-Norepinephrine Bitartrate

      To a four necked 100 ml flask charged racemic Norepinephrine base (20 gm), d-(−) tartaric acid (18.34 gm), and water (35 ml) at room temperature. The reaction mass was stirred to obtain clear solution, cooled to 0-5° C. After 5 hours slight turbidity was observed. Turbidity increases slowly to get thick white slurry after 6 hours, reaction mass becomes very thick which was difficult to filter, washed solid wet cake by 4.0 ml water followed by two 12 ml portions of 95% ethanol. Suck dried the solid completely, dried at 45° C. to get l-Norepinephrine Bitartrate (28 gm) which is in crude form.
      Crude l-Norepinephrine Bitartrate (20 gm) dissolved in 14 ml of water at 50° C. Clear solution was obtained. Activated charcoal was added to this solution and stirred the reaction mass for more for 30 min. Filtered through Hyflo and cooled to 0-5° C. After 2 hours, clear solution obtained gets converted to thick solid mass. Filtered and washed the solid with 1.5 ml of chilled water followed 14 ml of 95% ethanol.
      This dry solid 8 gm (after 1 st purification) was then dissolved in 8 ml of water at 50° C. to get clear solution. This reaction mass was then cooled to 0-5° C. After 1 hour, a clear solution gets converted to a thick solid mass. Maintained the reaction mass for more than 2 hours at the same conditions. Filtered the thick solid and washed with 95% ethanol. Dried the solid at 45° C. to obtain l-Norepinephrine Bitartrate.
      Chiral Purity by HPLC: l-Norepinephrine Bitartrate=68.45%, and d-isomer=31.55%
      Specific Optical Rotation: −6.33°

Reference Example-2 (JAGS, 1948, Page-2067-68, Example-a)

      To a four necked flask charged racemic Norepinephrine base (20 gm), d-(−) tartaric acid (18.34 gm), and water (35.20 ml) at room temperature. After 5 minutes reaction mass becomes clear liquid. Cooled the reaction mass to 2-3° C. After 30 minutes, reaction mass was observed to be turbid and further the reaction mass becomes very thick. This mass was, stirred for 2 hours at 0-5° C. Then filtered reaction mass at same temperature and washed solid wet cake with 3.5 ml water followed by two 11.8 ml portions of 95% ethanol. Dried the solid at air oven at 45° C. to get crude tartrate salt (15 gm).
      Crude tartrate salt (15 gm) was dissolved in 5 ml of water at 50° C. to get clear solution. Cooled to 2-3° C. After 30 minutes, a clear solution gets converted to a thick solid mass. Filtered the solid and washed with 1.5 ml of chilled water and then 15 ml of 95% ethanol. Dried the solid at 45° C. to obtain semi pure l-Norepinephrine Bitartrate (8 gm).
      This semi pure l-Norepinephrine Bitartrate (8 gm) was dissolved in 8 ml of water at 50° C. to get clear solution. Cooled the mass to 2-3° C. After 30 minutes clear solution gets converted to thick solid mass. Filtered the solid and washed with 8 ml of 95% ethanol. Dried the solid at 45° C. to obtain pure l-Norepinephrine Bitartrate (3 gm).
      Chiral Purity: l-Norepinephrine Bitartrate=77.14%, d-isomer=22.86%
      Specific Optical Rotation: −10.4°

Example-1: Preparation of 2-Chloro-1-(3, 4-Dihydroxyacetophenone)

      In round bottom flask, charged Methylene Chloride (1000 ml), Aluminium chloride (300 gm) and cooled to 0-5° C. Pyrocatechol (100 gm) was added lot wise. Chloroacetyl chloride (108 gm) was added drop wise at 0-5° C. Then stirred the reaction mass at 25-30° C. for 20-24 hours. After completion of the reaction, reaction mass was quenched in aq. HCl, filtered the reaction mass and wet cake was charged in water containing acetic acid. Filtered the reaction mass and cooled to 15-20° C., filtered solid and washed with water.
      Yield: 110 gm.
      HPLC Purity: 99.5%

Example-2: Preparation of Hexamine Salt

      In a round bottom flask charged 2-chloro-1-(3, 4-dihydroxyacetophenone) (100 gm), Hexamine (87 gm), IPA (500 ml), Chloroform (400 ml). Stirred the reaction mass at reflux temperature for 6 hours. After completion of the reaction, cooled to 25-30° C., filtered and washed the wet cake with IPA and Methanol.
      Yield: 160 gm.
      HPLC Purity: 99.3%

Example-3: Preparation of 2-Amino-1-(3,4-Dihydroxyphenyl)Ethanone Hydrochloride

      In a round bottom flask charged Hexamine salt (100 gm), Methanol (600 ml), aqueous HCl and heated the reaction mass to 55-60° C. After completion of the reaction, the mass was dissolved in water, by adjusting pH with liquor ammonia. Filtered the solid and washed with water, dried the material at 45-50° C.
      This free base was charged in 900 ml methanol and pH was adjusted to 1-1.5 by IPA.HCl and distilled off methanol completely to get white solid which was isolated by filtration.
      Yield: 37 gm
      HPLC Purity: 99.5%

Example-4: Preparation of [4-(2-Amino-1-Hydroxyethyl) Benzene-1, 2-Diol] (Racemic Norepinephrine Base)

      Charged 2-amino-1-(3, 4-dihydroxyphenyl) ethanone hydrochloride (100 gm), 10% Pd/C(10 gm), methanol (700 ml) and water (300 ml) mixture in autoclave. Stirred the reaction mass at 40-45° C. After completion of reaction, Pd/C was removed by filtration. Collected filtrate and distilled off methanol. pH was adjusted by liquor ammonia. Isolated the solid by filtration and washed with water followed by methanol. Dried the solid at 40-45° C.
      Yield: 67 gm
      Purity: 99.2%

Example-5: Preparation of l-Norepinephrine Base

      Charged racemic Norepinephrine base (100 gm), D-(−)-Tartaric acid (142 gm), water (100 ml) in a round bottom flask. The reaction mass was stirred to get clear solution. After some time, solid started to crystallize. Reaction mass was diluted with methanol (900 ml). Maintained the reaction mass under stirring for 24 hours at 25-30° C. Filtered and washed the wet cake with methanol to obtain Crude l-Norepinephrine tartrate salt.
      Yield: 85 gm
      The crude l-Norepinephrine tartrate salt was converted into its free base by dissolving this crude tartrate salt in water (500 ml) and adjusted pH to 8-8.5 by liquor ammonia and isolated the solid by filtration. Dried the material at 40-45° C. to obtain pure l-Norepinephrine free base (43 gm).
      Yield: 43 gm (l-Norepinephrine pure base).
      HPLC Purity: 99.7%
      Chiral Purity: 98.0%

Example-6: Preparation of Pure l-Norepinephrine Base

      Charged l-Norepinephrine base (100 gm) obtained from Example-5, D-(−)-Tartaric acid (142 gm), water (100 ml) in a round bottom flask. The reaction mass was stirred to get clear solution. After some time, a solid started to crystallize. Reaction mass was diluted with methanol (900 ml). Maintained the reaction mass under stirring for 24 hours at 25-30° C. Filtered and washed the wet cake with methanol to obtain l-Norepinephrine tartrate salt.
      Yield: 88 gm
      The l-Norepinephrine tartrate salt was converted into its free base by dissolving this crude tartrate salt in water (500 ml) and adjusted the pH to 8-8.5 by liquor ammonia and isolated the solid by filtration. Dried the material at 40-45° C. to obtain pure l-Norepinephrine free base (44 gm).
      Yield: 44 gm (l-Norepinephrine pure base).
      HPLC Purity: 99.7%
      Chiral Purity: 99.1%

Example-7: Preparation of Highly Pure Norepinephrine Bitartrate Monohydrate

      Charged Norepinephrine pure base (100 gm), L-(+) tartaric acid (100 gm), water (100 ml) and methanol (900 ml), Stirred the reaction mass to get clear solution. After some time, a solid started to crystallize then the reaction mass was diluted with methanol (900 ml). Maintained the reaction mass under stirring at 25-30° C. for 24 hours. Filtered and washed the wet cake with methanol to obtain Norepinephrine Bitartrate Monohydrate (90 gm).
      HPLC Purity: 99.8%
      Chiral Purity: 99.4%

Example-8: Purification of l-Norepinephrine Bitartrate Monohydrate

      Charged 100 gm tartrate salt obtained from example-6, purified water (100 ml) and heated the reaction mass to 40-45° C. to obtain clear solution, cooled to 0-5° C. Charged IPA (100 ml) slowly and the mass was stirred for one hour. The solid was isolated by filtration and washed with IPA. Dried the material at 40-45° C. to obtain l-Norepinephrine Bitartrate Monohydrate (82 gm) having high enantiomeric purity.
      HPLC Purity: 99.85%
      Chiral Purity: 99.87%
      Specific Optical rotation: −11.0°

Example-9

      The following table sets forth the high purity of the l-Norepinephrine Bitartrate monohydrate of the invention as compared with prior art references.
[TABLE-US-00001]   Referencel-Norepinephrine  Example-2Bitartrate U.S. Pat. No.(JACS, 1948,monohydrate 2,774,789Page-2067-68,of the presentPurity CriteriaExample-AExample-a)invention  Optical purity of l-68.45%77.14%99.87%NorepinephrineBitartratemonohydrateSpecific Optical−6.33°−10.4°−11.0°rotation(Limit: −10°to −12°) 
      It is evident from the above table that the compound of the present invention has substantially improved optical purity.

PATENTCN-102525895

Publication numberPriority datePublication dateAssigneeTitleCN101053557A *2006-04-132007-10-17邵长青Noradrenaline bitartrate medicine composition frozen dried powder injectionCN102335123A *2010-07-162012-02-01上海禾丰制药有限公司Noradrenaline bitartrate injection and preparation technology thereofPublication numberPriority datePublication dateAssigneeTitleEP3110399B12014-02-272018-01-10Sintetica S.A.Process for producing a stable low concentration, injectable solution of noradrenalineFamily To Family CitationsCN109394683A *2018-12-072019-03-01远大医药(中国)有限公司A kind of preparation method of noradrenaline bitartrate injection

References

  1. ^ Andersen, A. M. (1975). “Structural Studies of Metabolic Products of Dopamine. IV. Crystal and Molecular Structure of (−)-Noradrenaline”Acta Chem. Scand. 29b: 871–876. doi:10.3891/acta.chem.scand.29b-0871.
  2. Jump up to:a b c d e f g h i j “Norepinephrine Bitartrate”. The American Society of Health-System Pharmacists. Archived from the original on 26 March 2017. Retrieved 26 March 2017.
  3. ^ Latifi, Rifat (2016). Surgical Decision Making: Beyond the Evidence Based Surgery. Springer. p. 67. ISBN 9783319298245Archived from the original on 2017-03-27.
  4. ^ Encyclopedia of the Neurological Sciences. Academic Press. 2014. p. 224. ISBN 9780123851581Archived from the original on 2017-03-27.
  5. ^ Rhodes, Andrew; Evans, Laura E (March 2017). “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016” (PDF). Critical Care Medicine45 (3): 486–552. doi:10.1097/CCM.0000000000002255hdl:10281/267577PMID 28098591S2CID 52827184We recommend norepinephrine as the first-choice vasopressor (strong recommendation, moderate quality of evidence).
  6. ^ De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL (March 2010). “Comparison of dopamine and norepinephrine in the treatment of shock”. The New England Journal of Medicine362 (9): 779–89. doi:10.1056/nejmoa0907118PMID 20200382.
  7. ^ I Moore, Joanne (6 December 2012). Pharmacology (3 ed.). Springer Science and Business Media. p. 39. ISBN 9781468405248. Retrieved 19 November 2017.
  8. ^ “CV Physiology | Circulating Catecholamines”cvphysiology.com. Retrieved 2019-02-27.
  9. ^ Sacha, Pollard; Stephenie, B Edwin; Cesar, Alaniz (July 2015). “Vasopressor and Inotropic Management Of Patients With Septic Shock”Physical Therapy40 (7): 449–450. PMC 4495871PMID 26185405.

External links

Skeletal formula of noradrenaline
Ball-and-stick model of the zwitterionic form of noradrenaline found in the crystal structure[1]
Clinical data
Trade namesLevarterenol, Levophed, Norepin, other
Other namesNoradrenaline
(R)-(–)-Norepinephrine
l-1-(3,4-Dihydroxyphenyl)-2-aminoethanol
AHFS/Drugs.comMonograph
License dataUS DailyMedNorepinephrineUS FDANorepinephrine
Pregnancy
category
AU: B3
Routes of
administration
Intravenous
ATC codeC01CA03 (WHO)
Physiological data
Source tissuesLocus coeruleussympathetic nervous systemadrenal medulla
Target tissuesSystem-wide
Receptorsα1α2β1β3
AgonistsSympathomimetic drugsclonidineisoprenaline
AntagonistsTricyclic antidepressantsBeta blockersantipsychotics
MetabolismMAO-ACOMT
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
MetabolismMAO-ACOMT
ExcretionUrine (84–96%)
Identifiers
showIUPAC name
CAS Number51-41-2 
PubChem CID439260
IUPHAR/BPS505
DrugBankDB00368 
ChemSpider388394 
UNIIX4W3ENH1CV
KEGGD00076 as salt: D05206 
ChEBICHEBI:18357 
ChEMBLChEMBL1437 
Chemical and physical data
FormulaC8H11NO3
Molar mass169.180 g·mol−1
3D model (JSmol)Interactive image
Density1.397±0.06 g/cm3
Melting point217 °C (423 °F) (decomposes)
Boiling point442.6 °C (828.7 °F) ±40.0°C
hideSMILESOc1ccc(cc1O)[C@@H](O)CN
hideInChIInChI=1S/C8H11NO3/c9-4-8(12)5-1-2-6(10)7(11)3-5/h1-3,8,10-12H,4,9H2/t8-/m0/s1 Key:SFLSHLFXELFNJZ-QMMMGPOBSA-N 

////////Norepinephrine bitartrate, ARTERELOL, a-Adrenergic Agonist, Antihypotensive,  levarterenol, Adrenor,  Levophed,

#Norepinephrine bitartrate, #ARTERELOL, #a-Adrenergic Agonist, #Antihypotensive, #levarterenol, #Adrenor,  #Levophed,

O.O[C@H]([C@@H](O)C(O)=O)C(O)=O.NC[C@H](O)C1=CC(O)=C(O)C=C1


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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