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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 PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries...... , 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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Skeletal formula of triethylenetetramine


  • Molecular Formula C6H18N4
  • Average mass 146.234 Da

112-24-3 CAS

曲恩汀, KD-034, MK-0681, MK-681, TECZA, TETA, TJA-250

1,2-Ethanediamine, N1,N2-bis(2-aminoethyl)-
Image result for TRIENTINE


  • Molecular Formula C6H19ClN4
  • Average mass 182.695 Da

38260-01-4 CAS


Image result for MSD

Image result for VALEANT

Trientine Hydrochloride

C6H18N4▪2HCl : 219.16

Aton Pharma, a subsidiary of Valeant Pharmaceuticals, has developed and launched Syprine, a capsule formulation of trientine hydrochloride, for treating Wilson disease.

Image result for TRIENTINE

Triethylenetetramine, abbreviated TETA and trien and also called trientine (INN), is an organic compound with the formula [CH2NHCH2CH2NH2]2. This oily liquid is colorless but, like many amines, assumes a yellowish color due to impurities resulting from air-oxidation. It is soluble in polar solvents. The branched isomer tris(2-aminoethyl)amine and piperazine derivatives may also be present in commercial samples of TETA.[1]

Trientine hydrochloride is a metal antagonist that was first launched by Merck, Sharp & Dohme in the U.S. in 1986 under the brand name Syprine for the oral treatment of Wilson’s disease.

Orphan drug designation has also been assigned in the U.S. for the treatment of patients with Wilson’s disease who are intolerant or inadequately responsive to penicillamine and in the E.U. by Univar for the treatment of Wilson’s disease

 Trientine hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=90373

By condensation of ethylenediamine (I) with 1,2-dichloroethane (II)

Trientine hydrochloride is N,N’-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether.

The empirical formula is C6H18N4·2HCI with a molecular weight of 219.2. The structural formula is:


Trientine hydrochloride is a chelating compound for removal of excess copper from the body. SYPRINE (Trientine Hydrochloride) is available as 250 mg capsules for oral administration. Capsules SYPRINE contain gelatin, iron oxides, stearic acid, and titanium dioxide as inactive ingredients.

Image result for TRIENTINE


TETA is prepared by heating ethylenediamine or ethanolamine/ammonia mixtures over an oxide catalyst. This process gives a variety of amines, which are separated by distillation and sublimation.[2]


The reactivity and uses of TETA are similar to those for the related polyamines ethylenediamine and diethylenetriamine. It was primarily used as a crosslinker (“hardener”) in epoxy curing.[2]

The hydrochloride salt of TETA, referred to as trientine hydrochloride, is a chelating agent that is used to bind and remove copper in the body to treat Wilson’s disease, particularly in those who are intolerant to penicillamine. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.[3]

Coordination chemistry

TETA is a tetradentate ligand in coordination chemistry, where it is referred to as trien.[4] Octahedral complexes of the type M(trien)Cl3 can adopt several diastereomeric structures, most of which are chiral.[5]

Trientine, chemically known as triethylenetetramine or N,N’-bis(2-aminoethyl)-l,2-ethanediamine belongs to the class of polyethylene polyamines. Trientine dihydrochloride is a chelating agent which is used to bind and remove copper in the body in the treatment of Wilson’s disease.

Image result for TRIENTINE

Trientine dihydrochloride (1)

Trientine dihydrochloride formulation, developed by Aton with the proprietary name SYPRINE, was approved by USFDA on November 8, 1985 for the treatment of patients with Wilson’s disease, who are intolerant to penicillamine. Trientine dihydrochloride, due to its activity on copper homeostasis, is being studied for various potential applications in the treatment of internal organs damage in diabetics, Alzheimer’s disease and cancer.

Various synthetic methods for preparation of triethylenetetramine (TETA) and the corresponding dihydrochloride salt have been disclosed in the prior art.

U.S. 4,806,517 discloses the synthesis of triethylenetetramine from ethylenediamine and monoethanolamine using Titania supported phosphorous catalyst while U.S. 4,550,209 and U.S. 5,225,599 disclose catalytic condensation of ethylenediamine and ethylene glycol for the synthesis of linear triethylenetetramine using catalysts like zirconium trimethylene diphosphonate, or metatungstate composites of titanium dioxide and zirconium dioxide.

U.S. 4,503,253 discloses the preparation of triethylenetetramine by reaction of an alkanolamine compound with ammonia and an alkyleneamine having two primary amino groups in the presence of a catalyst, such as supported phosphoric acid wherein the support is comprised of silica, alumina or carbon.

The methods described above for preparation of triethylenetetramine require high temperatures and pressure. Further, due to the various possible side reactions and consequent associated impurities, it is difficult to control the purity of the desired amine.

CN 102924289 discloses a process for trientine dihydrochloride comprising reduction of Ν,Ν’-dibenzyl-,N,N’-bis[2-(l,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to give N,N’-dibenzyl-,N,N’-bis(2-aminoethyl)ethanediamine, which, upon condensation with benzyl chloroformate gave N,N’-dibenzyl-,N,N’-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to give the desired compound.

CS 197,093 discloses a process comprising reaction of triethylenetetramine with concentrated hydrochloric acid to obtain the crystalline tetrahydrochlonde salt. Further reaction of the salt with sodium ethoxide in solvent ethanol, filtration of the solid sodium chloride which is generated in the process, followed by slow cooling and crystallization of the filtrate provided the dihydrochloride salt. Optionally, aqueous solution of the tetrahydrochloride salt was passed through a column of an anion exchanger and the eluate containing free base was treated with a calculated amount of the tetrahydrochloride, evaporated, and the residue was crystallized from aqueous ethanol to yield the dihydrochloride salt.

The process is quite circuitous and cumbersome, requiring use of strong bases, filtration of sodium chloride and results in yields as low as 60%.

US 8,394,992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (boc) protected triethylenetetramine is first converted to its tetrahydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetrahydrochloride salt with a strong base like sodium alkoxide to produce the amine free base (TETA) and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether (TBME), followed by removal of sodium chloride salt and finally the amine free base TETA is treated with hydrochloric acid in solvent ethanol to give trientine hydrochloride salt.





Example 1: Preparation of 2-([2-[cyanomethyl]-t-butyloxycarbonylamino]ethyl- 1-butyloxy carbonylamino)acetonitrile (5)

Potassium carbonate (481.9 g) was added to a stirred mixture of ethylenediamine (100.0 g) in acetonitrile (800 ml) and cooled to around 10°C. Chloroacetonitrile (263.8 g) was gradually added at same temperature and stirred at 25-30°C, till completion of the reaction, as monitored by HPLC. The mixture was cooled to 5-15°C and Boc-anhydride (762. lg) was added to it, followed by stirring at the same temperature. The temperature was raised to 25-30°C and the mass was stirred till completion of the reaction, as monitored by HPLC.

The reaction mass was filtered and the filtrate was concentrated. Toluene was added to the residue, and the mixture was heated to around 70°C followed by cooling and filtration to give 2-([2-[cyanomethyl)-t-butyloxycarbonylamino]ethyl-t-butyloxycarbonylamino) acetonitrile (5).

Yield: 506.8 g

% Yield: 89.9 %

Example 2: Preparation of t-butyl( N-2-aminoethyl)N-([2-[(2-aminoethyl)t-butyloxy)carbonylamino] ethyl) carbamate (6)

Raney nickel (120.0 g) in isopropanol (100 ml) was charged into an autoclave, followed by a mixture of Compound 5 (200 g) in isopropanol (400 ml). Cooled ammonia solution prepared by purging ammonia gas in 1400 ml isopropanol, equivalent to 125 g ammonia was gradually charged to the autoclave and the reaction was carried out around 15-25°C under hydrogen pressure of 2-5 Kg/cm2.

After completion of the reaction, as monitored by HPLC, the mass was filtered, concentrated, and methyl tertiary butyl ether was added to the residue. The mixture was heated to around 50°C, followed by cooling of the mass, stirring, optional seeding with compound 6 and filtration to give tertiary butyl-(N-2-aminoethyl)N-([2-[(2-aminoethyl)-(tert-butyloxy) carbonylamino] ethyl) carbamate.

Yield: 174 g

%Yield: 85 %

Example 3: Preparation of triethylenetetramine dihydrochloride (1)

Concentrated hydrochloric acid (121.5 g) was gradually added to a stirred mixture of tertiary-butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy) carbonyl] amino] ethyl} carbamate (Compound 6, 200.0 g) and water (1400 ml) at 20-30°C. The reaction mixture was heated in the temperature range of 100-105°C till completion of the reaction, as monitored by HPLC, with optionally distilling out water, if so required.

The reaction mass was concentrated and ethanol (600 ml) was added to the residue, followed by heating till a clear solution was obtained. The reaction mixture was gradually cooled with stirring, filtered and dried to provide triethylenetetramine dihydrochloride (1).

Yield: 88.9 g, (70 %)

Purity : > 99%


Trientine was said to be used in the synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine in French Patent No. FR2810035 to Guilard et al. Cetinkaya, E., et al., “Synthesis and characterization of unusual tetraminoalkenes,” J. Chem. Soc. 5:561-7 (1992), is said to be directed to synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine from trientine, as is Araki T., et al., “Site-selective derivatization of oligoethyleneimines using five-membered-ring protection method,” Macromol., 21:1995-2001 (1988). Triethylenetetramine may reportedly also be used in the synthesis of N-methylated triethylenetetramine, as reported in U.S. Pat. No. 2,390,766, to Zellhoefer et al.

Synthesis of polyethylenepolyamines, including triethylenetetramines, from ethylenediamine and monoethanolamine using pelleted group IVb metal oxide-phosphate type catalysts was reported by Vanderpool et al. in U.S. Pat. No. 4,806,517. Synthesis of triethylenetetramine from ethylenediamine and ethanolamine was also proposed in U.S. Pat. No. 4,550,209, to Unvert et al. U.S. Pat. No. 5,225,599, to King et al. is said to be directed to the synthesis of linear triethylene tetramine by condensation of ethylenediamine and ethylene glycol in the presence of a catalyst. Joint production of triethylenetetramine and 1-(2-aminoethyl)-aminoethyl-piperazine was proposed by Borisenko et al. in U.S.S.R. Patent No. SU1541204. U.S. Pat. No. 4,766,247 and European Patent No. EP262562, both to Ford et al., reported the preparation of triethylenetetramine by reaction of an alkanolamine compound, an alkaline amine and optionally either a primary or secondary amine in the presence of a phosphorous containing catalyst, for example phosphoric acid on silica-alumina or Group IIIB metal acid phosphate, at a temperature from about 175° C. to 400° C. under pressure. These patents indicate that the synthetic method used therein was as set forth in U.S. Pat. No. 4,463,193, to Johnson. The Ford et al. ‘247 patent is also said to be directed to color reduction of polyamines by reaction at elevated temperature and pressure in the presence of a hydrogenation catalyst and a hydrogen atmosphere. European Patent No. EP450709 to King et al. is said to be directed to a process for the preparation of triethylenetetramine and N-(2-aminoethyl)ethanolamine by condensation of an alkylenamine and an alkylene glycol in the presence of a condensation catalyst and a catalyst promoter at a temperature in excess of 260° C.

Russian Patent No. RU2186761, to Zagidullin, proposed synthesis of diethylenetriamine by reaction of dichloroethane with ethylenediamine. Ethylenediamine has previously been said to have been used in the synthesis of N-carboxylic acid esters as reported in U.S. Pat. No. 1,527,868, to Hartmann et al.

Japanese Patent No. 06065161 to Hara et al. is said to be directed to the synthesis of polyethylenepolyamines by reacting ethylenediamine with ethanolamine in the presence of silica-treated Nb205 supported on a carrier. Japanese Patent No. JP03047154 to Watanabe et al., is said to be directed to production of noncyclic polyethylenepolyamines by reaction of ammonia with monoethanolamine and ethylenediamine. Production of non-cyclic polyethylenepolyamines by reaction of ethylenediamine and monoethanolamine in the presence of hydrogen or a phosphorous-containing substance was said to be reported in Japanese Patent No. JP03048644. Regenerative preparation of linear polyethylenepolyamines using a phosphorous-bonded catalyst was proposed in European Patent No. EP115,138, to Larkin et al.

A process for preparation of alkyleneamines in the presence of a niobium catalyst was said to be provided in European Patent No. 256,516, to Tsutsumi et al. U.S. Pat. No. 4,584,405, to Vanderpool, reported the continuous synthesis of essentially noncyclic polyethylenepolyamines by reaction of monoethanolamine with ethylenediamine in the presence of an activated carbon catalyst under a pressure between about 500 to about 3000 psig., and at a temperature of between about 200° C. to about 400° C. Templeton, et al., reported on the preparation of linear polyethylenepolyamides asserted to result from reactions employing silica-alumina catalysts in European Patent No. EP150,558.

Production of triethylenetetramine dihydrochloride was said to have been reported in Kuhr et al., Czech Patent No. 197,093, via conversion of triethylenetetramine to crystalline tetrahydrochloride and subsequently to triethylenetetramine dihydrochloride. “A study of efficient preparation of triethylenetetramine dihydrochloride for the treatment of Wilson’s disease and hygroscopicity of its capsule,” Fujito, et al., Yakuzaigaku, 50:402-8 (1990), is also said to be directed to production of triethylenetetramine.

Preparation of triethylenetetramine salts used for the treatment of Wilson’s disease was said to be reported in “Treatment of Wilson’s Disease with Triethylene Tetramine Hydrochloride (Trientine),” Dubois, et al., J. Pediatric Gastro. & Nutrition, 10:77-81 (1990); “Preparation of Triethylenetetramine Dihydrochloride for the Treatment of Wilson’s Disease,” Dixon, et al., Lancet, 1(1775):853 (1972); “Determination of Triethylenetetramine in Plasma of Patients by High-Performance Liquid Chromatography,” Miyazaki, et al., Chem. Pharm. Bull., 38(4):1035-1038 (1990); “Preparation of and Clinical Experiences with Trien for the Treatment of Wilson’s Disease in Absolute Intolerance of D-penicillamine,” Harders, et al., Proc. Roy. Soc. Med., 70:10-12 (1977); “Tetramine cupruretic agents: A comparison in dogs,” Allen, et al., Am. J. Vet. Res., 48(1):28-30 (1987); and “Potentiometric and Spectroscopic Study of the Equilibria in the Aqueous Copper(II)-3,6-Diazaoctane-1,8-diamine System,” Laurie, et al., J.C.S. Dalton, 1882 (1976).

Preparation of Triethylenetetramine Salts by Reaction of Alcohol Solutions of Amines and acids was said to be reported in Polish Patent No. 105793, to Witek. Preparation of triethylenetetramine salts was also asserted in “Polycondensation of polyethylene polyamines with aliphatic dicarboxylic acids,” Witek, et al., Polimery, 20(3):118-119 (1975).

Baganz, H., and Peissker, H., Chem. Ber., 1957; 90:2944-2949; Haydock, D. B., and Mulholland, T. P. C., J. Chem. Soc., 1971; 2389-2395; and Rehse, K., et al., Arch. Pharm., 1994; 393-398, report on Strecker syntheses. Use of Boc and other protecting groups has been described. See, for example, Spicer, J. A. et al., Bioorganic & Medicinal Chemistry, 2002; 10: 19-29; Klenke, B. and Gilbert, I. H., J. Org. Chem., 2001; 66: 2480-2483.

FIG. 6 shows an 1H-NMR spectrum of a triethylenetetramine hydrochloride salt in D2O, as synthesized in Example 3. NMR values include a frequency of 400.13 Mhz, a 1H nucleus, number of transients is 16, points count of 32768, pulse sequence of zg30, and sweep width of 8278.15 H

Image result for TRIENTINE


Method of purification: Dissolve Trientine Hydrochloride in water while warming, and recrystallize by addition of ethanol (99.5). Or dissolve Trientine Hydrochloride in water while warming, allow to stand after addition of activated charcoal in a cool and dark place for one night, and filter. To the filtrate add ethanol (99.5), allow to stand in a cool and dark place, and recrystallize. Dry the crystals under reduced pressure not exceeding 0.67 kPa at 409C until ethanol odor disappears.


  1.  “Ethyleneamines” (PDF). Huntsman. 2007.
  2. ^ Jump up to:a b Eller, K.; Henkes, E.; Rossbacher, R.; Höke, H. (2005). “Amines, Aliphatic”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_001.
  3. Jump up^ Roberts, E. A.; Schilsky, M. L. (2003). “A practice guideline on Wilson disease” (pdf). Hepatology. 37 (6): 1475–1492. doi:10.1053/jhep.2003.50252. PMID 12774027.
  4. Jump up^ von Zelewsky, A. (1995). Stereochemistry of Coordination Compounds. Chichester: John Wiley. ISBN 047195599X.
  5.  Utsuno, S.; Sakai, Y.; Yoshikawa, Y.; Yamatera, H. (1985). “Three Isomers of the Trans-Diammine-[N,N′-bis(2-Aminoethyl)-1,2-Ethanediamine]-Cobalt(III) Complex Cation”. Inorganic Syntheses. 23: 79–82. doi:10.1002/9780470132548.ch16.
Skeletal formula of triethylenetetramine
Ball and stick model of triethylenetetramine
Spacefill model of triethylenetetramine
Other names

N,N’-Bis(2-aminoethyl)ethane-1,2-diamine; TETA; Trien; Trientine (INN); Syprine (brand name)
3D model (Jmol)
ECHA InfoCard 100.003.591
EC Number 203-950-6
MeSH Trientine
RTECS number YE6650000
UN number 2259
Molar mass 146.24 g·mol−1
Appearance Colorless liquid
Odor Fishy, ammoniacal
Density 982 mg mL−1
Melting point −34.6 °C; −30.4 °F; 238.5 K
Boiling point 266.6 °C; 511.8 °F; 539.7 K
log P 1.985
Vapor pressure <1 Pa (at 20 °C)
376 J K−1 mol−1 (at 60 °C)
A16AX12 (WHO)
GHS pictograms The corrosion pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) The exclamation-mark pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
GHS signal word DANGER
H312, H314, H317, H412
P273, P280, P305+351+338, P310
Corrosive C
R-phrases R21, R34, R43, R52/53
S-phrases (S1/2), S26, S36/37/39, S45
Flash point 129 °C (264 °F; 402 K)
Lethal dose or concentration (LD, LC):
  • 550 mg kg−1 (dermal, rabbit)
  • 2.5 g kg−1 (oral, rat)
Related compounds
Related amines
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////////TRIENTINE, 112-24-3, 曲恩汀 , KD-034 , MK-0681, MK-681, TECZA, TETA, TJA-250, Orphan drug



Calcifediol, カルシフェジオール

Skeletal formula of calcifediol



Ro 8-8892
U 32070E
(3S,5Z,7E,20R)-9,10-Secocholesta-5,7,10-trien-3,25-diol [German] [ACD/IUPAC Name]
(3S,5Z,7E,20R)-9,10-Secocholesta-5,7,10-triene-3,25-diol [ACD/IUPAC Name]
(3S,5Z,7E,20R)-9,10-Sécocholesta-5,7,10-triène-3,25-diol [French] [ACD/IUPAC Name]
19356-17-3 [RN]
1H-indene-1-pentanol, octahydro-4-[(2Z)-2-[(5S)-5-hydroxy-2-methylenecyclohexylidene]ethylidene]-a,a,e,7a-tetramethyl-, (eR,1R,3aS,4E,7aR)-
25-(OH)Vitamin D3
25-hydroxy Vitamin D3
25-hydroxyvitamin D
Molecular form.: C₂₇H₄₄O₂
Appearance: White to Off-White Solid
Melting Point: 75-93ºC
Mol. Weight: 400.64

Calcifediol (INN), also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D (abbreviated 25(OH)D),[1] is a prehormone that is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme cholecalciferol 25-hydroxylase which was isolated by Michael F. Holick. Physicians worldwide measure this metabolite to determine a patient’s vitamin D status.[2] At a typical daily intake of vitamin D3, its full conversion to calcifediol takes approximately 7 days.[3]

Calcifediol is then converted in the kidneys (by the enzyme 25(OH)D-1α-hydroxylase) into calcitriol (1,25-(OH)2D3), a secosteroid hormone that is the active form of vitamin D. It can also be converted into 24-hydroxycalcidiol in the kidneys via 24-hydroxylation.[4][5]


Blood test

In medicine, a 25-hydroxy vitamin D (calcifediol) blood test is used to determine how much vitamin D is in the body.[6] The blood concentration of calcifediol is considered the best indicator of vitamin D status.[7]

This test can be used to diagnose vitamin D deficiency, and it is indicated in patients with high risk for vitamin D deficiency and when the results of the test would be used as supporting evidence for beginning aggressive therapies.[8] Patients with osteoporosis, chronic kidney disease, malabsorption, obesity, and some other infections may be high risk and thus have greater indication for this test.[8] Although vitamin D deficiency is common in some populations including those living at higher latitudes or with limited sun exposure, the 25(OH)D test is not indicated for entire populations.[8] Physicians may advise low risk patients to take over-the-counter vitamin D in place of having screening.[8]

It is the most sensitive measure,[9] though experts have called for improved standardization and reproducibility across different laboratories.[7] According to MedlinePlus, the normal range of calcifediol is 30.0 to 74.0 ng/mL.[6] The normal range varies widely depending on several factors, including age and geographic location. A broad reference range of 20–150 nmol/L (8-60 ng/ml) has also been suggested,[10] while other studies have defined levels below 80 nmol/L (32 ng/ml) as indicative of vitamin D deficiency.[11]

US labs generally report 25(OH)D levels as ng/mL. Other countries often use nmol/L. Multiply ng/mL by 2.5 to convert to nmol/L.

Clinical significance

Increasing calcifediol levels are associated with increasing fractional absorption of calcium from the gut up to levels of 80 nmol/L (32 ng/mL).[citation needed]Urinary calcium excretion balances intestinal calcium absorption and does not increase with calcifediol levels up to ~400 nmol/L (160 ng/mL).[12]

A study by Cedric F. Garland and Frank C. Garland of the University of California, San Diego analyzed the blood from 25,000 volunteers from Washington County, Maryland, finding that those with the highest levels of calcifediol had a risk of colon cancer that was one-fifth of typical rates.[13] However, randomized controlled trials failed to find a significant correlation between vitamin D supplementation and the risk of colon cancer.[14]

A 2012 registry study of the population of Copenhagen, Denmark, found a correlation between both low and high serum levels and increased mortality, with a level of 50–60 nmol/L being associated with the lowest mortality. The study did not show causation.[15][16]


Regioselective Hydroxylation in the Production of 25-Hydroxyvitamin D by Coprinopsis cinerea Peroxygenase
ChemCatChem (2015), 7, (2), 283-290

1H NMR 500 MHz, CDCl3: δ= 0.55 (3 H, s, 18-H), 0.94 (1H, d, J= 6.5 Hz, 21-H), 1.06 (1H, m, 22-H), 1.22 (3 H, s, 26-H), 1.22 (3 H, s, 27-H), 1.23 (1H, m, 23-H), 1.27 (1H, m, 16-H), 1.28 (1H, m, 14-H), 1.29 (1H, m, 12-H), 1.37 (1H, m, 22-H), 1.38 (1H, m, 20-H), 1.39 (1H, m, 24-H), 1.42 (1H, m, 23-H), 1.44 (1H, m, 24-H), 1.47 (2 H, m, 11-H), 1.53 (1H, m, 15-H), 1.66 (1H, m, 15-H), 1.67 (1H, m, 2-H), 1.67 (1H, m, 9-H), 1.87 (1H, m, 16-H), 1.92 (1H, m, 2-H), 1.98 (1H, m, 17-H), 2.06 (1H, m, 12-H), 2.17 (1H, m, 1-H), 2.40 (1H, m, 1-H), 2.57 (1H, dd, J= 3.7, 13.1Hz, 4-H), 2.82 (1H, m, 9-H), 3.95 (1H, bm, 3-H), 4.82 (1H, m, 19-H), 5.05 (1H, m, 19-H), 6.03 (1H, d, J=11.2 Hz, 7-H), 6.23 ppm (1H, d, J= 11.2 Hz, 6-H).

13 C NMR 500 MHz, CDCl3: δ = 12.2 (C-18), 19.0 (C-21), 21.0 (C-23), 22.4 (C-11), 23.7 (C-15), 27.8 (C-16), 29.2 (C-9), 29.4 (C-27), 29.5 (C-26), 32.1 (C-1), 35.3 (C-2), 36.3 (C-20), 36.6 (C-22), 40.7 (C-12), 44.6 (C-24), 46.0 (C-13), 46.1 (C-4), 56.5 (C-17), 56.7 (C-14), 69.4 (C-3), 71.3 (C-25), 112.6 (C-19), 117.7 (C-7), 122.2 (C-6), 135.2 (C-5), 142.4 (C-8), 145.3 ppm (C-10).


From Organic & Biomolecular Chemistry, 10(27), 5205-5211; 2012!divAbstract

An efficient, two-stage, continuous-flow synthesis of 1α,25-(OH)2-vitamin D3 (activated vitamin D3) and its analogues was achieved. The developed method afforded the desired products in satisfactory yields using a high-intensity and economical light source, i.e., a high-pressure mercury lamp. In addition, our method required neither intermediate purification nor high-dilution conditions.

Graphical abstract: Continuous-flow synthesis of activated vitamin D3 and its analogues

1H NMR(400 MHz, CDCl3): δ 8.13 (m, 2H), 7.68 (m, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 8.3 Hz, 1H), 5.19 (m, 2H), 3.93 (dd, J = 12.7, 8.2, 1H), 3.88 (dd, J = 14.6, 4.9 Hz, 1H), 3.58 (m, 1H), 1.02 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.86 (s, 9H), 0.80-0.84 (m, 9H), 0.09 (s, 3H), 0.00 (s, 3H)

13C NMR  (100 MHz, CDCl3): δ 161.8, 159.6, 138.5, 135.3, 132.6, 132.5, 132.1, 130.6, 130.2, 128.7, 127.0, 126.5, 77.2, 68.5, 67.4, 67.1, 56.5, 50.6, 49.0, 44.2, 42.7, 40.4, 39.9, 39.3, 35.6, 34.7, 33.0, 30.5, 28.2, 25.9, 24.5, 21.9, 20.8, 19.9, 19.7, 18.5, 18.0, 17.4, 13.3, -4.4, -4.9

IR (neat): 2957, 2872, 1653, 1603, 1462, 1311, 1093, 837, 762 cm-1


Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]



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|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway]

Vitamin D Synthesis Pathway edit

  1. Jump up^ The interactive pathway map can be edited at WikiPathways: “VitaminDSynthesis_WP1531”.


  1. Jump up^ “Nomenclature of Vitamin D. Recommendations 1981. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN)” reproduced at the Queen Mary, University of London website. Retrieved 21 March 2010.
  2. Jump up^ Holick, MF; Deluca, HF; Avioli, LV (1972). “Isolation and identification of 25-hydroxycholecalciferol from human plasma”. Archives of Internal Medicine. 129 (1): 56–61. doi:10.1001/archinte.1972.00320010060005. PMID 4332591.
  3. Jump up^ Am J Clin Nutr 2008;87:1738–42 PMID 18541563
  4. Jump up^ Bender, David A.; Mayes, Peter A (2006). “Micronutrients: Vitamins & Minerals”. In Victor W. Rodwell; Murray, Robert F.; Harper, Harold W.; Granner, Darryl K.; Mayes, Peter A. Harper’s Illustrated Biochemistry. New York: Lange/McGraw-Hill. pp. 492–3. ISBN 0-07-146197-3. Retrieved December 10, 2008 through Google Book Search.
  5. Jump up^ Institute of Medicine (1997). “Vitamin D”. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, D.C: National Academy Press. p. 254. ISBN 0-309-06403-1.
  6. ^ Jump up to:a b “25-hydroxy vitamin D test: Medline Plus”. Retrieved 21 March 2010.
  7. ^ Jump up to:a b Heaney, Robert P (Dec 2004). “Functional indices of vitamin D status and ramifications of vitamin D deficiency”. American Journal of Clinical Nutrition. 80 (6): 1706S–9S. PMID 15585791.
  8. ^ Jump up to:a b c d American Society for Clinical Pathology, “Five Things Physicians and Patients Should Question”, Choosing Wisely: an initiative of the ABIM Foundation, American Society for Clinical Pathology, retrieved August 1, 2013, which cites
      • Sattar, N.; Welsh, P.; Panarelli, M.; Forouhi, N. G. (2012). “Increasing requests for vitamin D measurement: Costly, confusing, and without credibility”. The Lancet. 379 (9811): 95–96. doi:10.1016/S0140-6736(11)61816-3. PMID 22243814.
      • Bilinski, K. L.; Boyages, S. C. (2012). “The rising cost of vitamin D testing in Australia: Time to establish guidelines for testing”. The Medical Journal of Australia. 197 (2): 90. doi:10.5694/mja12.10561. PMID 22794049.
      • Lu, Chuanyi M. (May 2012). “Pathology consultation on vitamin D testing: Clinical indications for 25(OH) vitamin D measurement [Letter to the editor]”. American Journal Clinical Pathology. American Society for Clinical Pathology (137): 831–832., which cites
        • Arya, S. C.; Agarwal, N. (2012). “Pathology Consultation on Vitamin D Testing: Clinical Indications for 25(OH) Vitamin D Measurement”. American Journal of Clinical Pathology. 137 (5): 832. doi:10.1309/AJCP2GP0GHKQRCOE. PMID 22523224.
      • Holick, M. F.; Binkley, N. C.; Bischoff-Ferrari, H. A.; Gordon, C. M.; Hanley, D. A.; Heaney, R. P.; Murad, M. H.; Weaver, C. M. (2011). “Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline”. Journal of Clinical Endocrinology & Metabolism. 96 (7): 1911–1930. doi:10.1210/jc.2011-0385. PMID 21646368.
  9. Jump up^ Institute of Medicine (1997), p. 259
  10. Jump up^ Bender, David A. (2003). “Vitamin D”. Nutritional biochemistry of the vitamins. Cambridge: Cambridge University Press. ISBN 0-521-80388-8. Retrieved December 10, 2008 through Google Book Search.
  11. Jump up^ Hollis BW (February 2005). “Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D”. J Nutr. 135 (2): 317–22. PMID 15671234.
  12. Jump up^ Kimball; et al. (2004). “Safety of vitamin D3 in adults with multiple sclerosis”. J Clin Endocrinol Metab. 86 (3): 645–51. PMID 17823429.
  13. Jump up^ Maugh II, Thomas H. “Frank C. Garland dies at 60; epidemiologist helped show importance of vitamin D: Garland and his brother Cedric were the first to demonstrate that vitamin D deficiencies play a role in cancer and other diseases.”, Los Angeles Times, August 31, 2010. Accessed September 4, 2010.
  14. Jump up^ Wactawski-Wende, J; Kotchen, JM, Women’s Health Initiative Investigators (Mar 9, 2006). “Calcium plus vitamin D supplementation and the risk of colorectal cancer.”. N Engl J Med. 354 (7): 684–96. doi:10.1056/NEJMoa055222. PMID 16481636. Retrieved December 28, 2013.
  15. Jump up^ “Too much vitamin D can be as unhealthy as too little” (Press release). University of Copenhagen. May 29, 2012. Retrieved 2015-05-27.
  16. Jump up^ Durup, D.; Jørgensen, H. L.; Christensen, J.; Schwarz, P.; Heegaard, A. M.; Lind, B. (May 9, 2012). “A Reverse J-Shaped Association of All-Cause Mortality with Serum 25-Hydroxyvitamin D in General Practice: The CopD Study”. The Journal of Clinical Endocrinology & Metabolism. Endocrine Society. 97 (8): 2644–2652. doi:10.1210/jc.2012-1176. Retrieved 2015-05-27.
Skeletal formula of calcifediol
Ball-and-stick model of the calcifediol molecule
IUPAC names

Other names

25-Hydroxyvitamin D3
19356-17-3 Yes
3D model (Jmol) Interactive image
ChEBI CHEBI:17933 
ChemSpider 4446820 
DrugBank DB00146 Yes
ECHA InfoCard 100.039.067
MeSH Calcifediol
PubChem 5283731
Molar mass 400.64 g/mol
A11CC06 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).


Title: Calcifediol
CAS Registry Number: 19356-17-3
CAS Name: (3b,5Z,7E)-9,10-Secocholesta-5,7,10(19)-triene-3,25-diol
Additional Names: 25-hydroxyvitamin D3; 25-hydroxycholecalciferol; 25-HCC
Manufacturers’ Codes: U-32070E
Trademarks: Dedrogyl (DESMA); Didrogyl (Bruno); Hidroferol (FAES)
Molecular Formula: C27H44O2
Molecular Weight: 400.64
Percent Composition: C 80.94%, H 11.07%, O 7.99%
Literature References: The principal circulating form of vitamin D3, formed in the liver by hydroxylation at C-25: Ponchon, DeLuca, J. Clin. Invest. 48, 1273 (1969). It is the intermediate in the formation of 1a,25-dihydroxycholecalciferol, q.v., the biologically active form of vitamin D3 in the intestine. Identification in rat as an active metabolite of vitamin D3: Lund, DeLuca, J. Lipid Res. 7, 739 (1966); Morii et al., Arch. Biochem. Biophys. 120, 513 (1967). Evaluation of biological activity in comparison with vitamin D3: Blunt et al., Proc. Natl. Acad. Sci. USA 61, 717 (1968); ibid. 1503. Isoln from porcine plasma and establishment of structure: Blunt et al., Biochemistry 7, 3317 (1968). Synthesis: Blunt, DeLuca, ibid. 8, 671 (1969). Review of isoln, identification and synthesis: DeLuca, Am. J. Clin. Nutr. 22, 412 (1969). Review of bioassays: J. G. Haddad Jr., Basic Clin. Nutr. 2, 579-597 (1980).
Properties: uv max (ethanol): 265 nm (e 18000) (Blunt, DeLuca).
Absorption maximum: uv max (ethanol): 265 nm (e 18000) (Blunt, DeLuca)
Therap-Cat: Calcium regulator.
Keywords: Calcium Regulator.

/////////Calcifediol, カルシフェジオール



Balsalazide structure.svg


80573-04-2; Colazal; Balsalazide Disodium; AC1NSFNR; P80AL8J7ZP;
Molecular Formula: C17H15N3O6
Molecular Weight: 357.322 g/mol

(3E)-3-[[4-(2-carboxyethylcarbamoyl)phenyl]hydrazinylidene]-6-oxocyclohexa-1,4-diene-1-carboxylic acid


CAS Number 150399-21-6
Weight Average: 437.316
Monoisotopic: 437.08110308
Chemical Formula C17H17N3Na2O8

Balsalazide is an anti-inflammatory drug used in the treatment of inflammatory bowel disease. It is sold under the brand names Giazo, Colazal in the US and Colazide in the UK. It is also sold in generic form in the US by several generic manufacturers.

It is usually administered as the disodium salt. Balsalazide releases mesalazine, also known as 5-aminosalicylic acid, or 5-ASA,[1] in the large intestine. Its advantage over that drug in the treatment of ulcerative colitis is believed to be the delivery of the active agent past the small intestine to the large intestine, the active site of ulcerative colitis.

Balsalazide is an anti-inflammatory drug used in the treatment of Inflammatory Bowel Disease. It is sold under the name “Colazal” in the US and “Colazide” in the UK. The chemical name is (E)-5-[[-4-(2-carboxyethyl) aminocarbonyl] phenyl]azo] –2-hydroxybenzoic acid. It is usually administered as the disodium salt. Balsalazide releases mesalazine, also known as 5-aminosalicylic acid, or 5-ASA, in the large intestine. Its advantage over that drug in the treatment of Ulcerative colitis is believed to be the delivery of the active agent past the small intestine to the large intestine, the active site of ulcerative colitis.

Balsalazide disodium and its complete synthesis was first disclosed by Chan[18] in 1983, assigned to Biorex Laboratories Limited, England, claiming product ‘Balsalazide’ and process of its preparation. The synthesis involves converting 4-nitrobenzoyl chloride (6) to 4- nitrobenzoyl-β-alanine (7), hydrogenating with Pd/C (5%) in ethanol and isolating by adding diethyl ether to produce 4-aminobenzoyl-β-alanine (8). Thereafter, 4-aminobenzoyl-β-alanine (8) was treated with hydrochloric acid and sodium nitrite to generate N-(4-diazoniumbenzoyl)- β-alanine hydrochloride salt (9) which was reacted at low temperature with disodium salicylate to furnish Balsalazide disodium insitu which was added to dilute hydrochloric acid at low temperature to produce Balsalazide (1) (Scheme-1.1). Thus obtained Balsalazide was recrystallized with hot ethanol and converted to pharmaceutically acceptable salt (disodium salt).

Optimization of this diazonium salt based process was performed by Huijun et al[19] and reported the preparation of the title compound in 64.6% overall yield. Zhenhau et al[20] have synthesized 1 from 4-nitrobenzoic acid (12) via chlorination, condensation, hydrogenation, diazotization, coupling and salt formation with overall yield 73%. Li et al[21] have given product in 73.9% total yield starting from 4-nitrobenzoyl chloride (6), where as Yuzhu et al[22] confirmed chemical structure of Balsalazide disodium by elemental analysis, UV, IR, 1H-NMR and ESI-MS etc. Shaojie et al[23] have also followed same process for its preparation. Yujie et al[24] synthesized 1 in this way; preparation of 4-nitrobenzoyl-β-alanine (7) under microwave irradiation of 420 W at 52oC for 10sec., reduction in ethyl acetate in the presence of Pd/C catalyst then diazotization, coupling and salt formation. Eckardt et al[25] have developed a process for the preparation of Balsalazide which comprises, conversion of 4-aminobenzoyl-β-alanine (8) to 4-ammoniumbenzoyl-β-alanine sulfonate salt using a sulfonic acid in water. This was treated with aq. sodium nitrite solution at low temperature to generate 4-diazoniumbenzoyl-β-alanine sulfonate salt (11) which was quenched with aq. disodium salicylate to furnish Balsalazide disodium solution. This was further acidified to allow isolation of 1 and then conversion to disodium salt (Scheme-1.2) in 76% yield.

IR (KBr, cm-1 ): 3371 and 3039 (OH and NH), 1705 and 1699 (C=O), 1634 (C=O amide), 1590 and 1538 (C=C aromatic), 1464 and 1404 (aliphatic C-H), 1229 (C-N), 1073 (C-O), 773 and 738 (Ar-H out of plane bend). 1H NMR (DMSO-d6, 300 MHz, δ ppm): 2.54 (t, 2H), 3.50 (m, 2H), 6.95 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.95 (dd, J = 8.8 Hz and 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.68 (t, J = 5.5 Hz, 1H), 12.12 (brs, 1H). MS m/z (ESI): 356 [(M-H)- ], Calculated; m/z 357.


Balsalazide synthesis: Biorex Laboratories, GB 2080796 (1986).

  1. Starting material is 4-aminohippuric acid, obtained by coupling para-aminobenzoic acid and glycine.
  2. That product is then treated with nitrous acid to give the diazonium salt.
  3. Reaction of this species with salicylic acid proceeds at the position para to the phenol to give balsalazide.

Sodium balsalazide (Balsalazide sodium)

Brief background information

Salt ATC Formula MM CAS
A07EC04 C 17 H 13 N 3 Na 2 O 6 401.29 g / mol 82101-18-6
(E) is the free acid A07EC04 C 17 H 15 N 3 O 6 357.32 g / mol 80573-04-2A


  • resolvent

Classes substance

  • β-alanine (3-aminopropionic acid)
    • m-aminobenzoic acid and esters and amides thereof
      • p-aminobenzoic acid and esters and amides thereof
        • azobenzene
          • salicylic acid

Synthesis Way

Synthesis of a)

Trade names

A country Tradename Manufacturer
United Kingdom Kolazid Shire
Italy Balzid Menarini
USA Kolazal Salix
Ukraine no no


  • capsules in 750 mg (as disodium salt)


Balsalazide disodium (1) represents an effective gastrointestinal anti-inflammatory compound useful as a medicament for the treatment of diseases such as ulcerative colitis. It is delivered intact to the colon where it is cleaved by bacterial azoreduction thereby generating 5-aminosalicylic acid as the medicinally active component.

Figure US07271253-20070918-C00001

To date, relatively few patents or literature articles have dealt with the preparation of Balsalazide or the disodium salt. For instance, U.S. Pat. No. 4,412,992 (Biorex, 1983) is the first patent that we uncovered that claims the compound Balsalazide and a strategy of how to prepare it which strategy is depicted in Scheme 1.

Figure US07271253-20070918-C00002

Optimization of this diazonium-based process is detailed in Shan et al., Zhongguo Yaowu Huaxue Zazhi, 11, 110 (2001) and Shi et al., Zhongguo Yiyao Gongye Zazhi, 34, 537 (2003).

Problems arise with the above strategy and the optimization process.

It is well-documented in the literature, for instance in Thermochimica Acta, 225, 201-211 (1993), that diazonium salts can be involved in serious accidents in their use. A possible cause of some of the diazonium salt related accidents is that, for one reason or another, an intermediate material appeared in crystalline form in the vessel of the reaction. As a result, a potentially severe drawback of the above processes occurs. Since the intermediate hydrochloride salt of 4-aminobenzoyl-β-alanine has poor solubility in water, it may pose a safety-risk in the subsequent diazotation reaction.

Also, it is well-known that certain diazonium salts possess high mechanical and heat sensitivity and that their decomposition goes through the liberation of non-condensable nitrogen gas which results in the possibility of runaway reactions and explosions. Obviously this safety consideration becomes more pertinent upon further scale-up.

Therefore, for commercial production of Balsalazide disodium, there was a need to develop a scalable and intrinsically better process

Example 1 Batch Process

N-(4-Aminobenzoyl)-β-alanine (100 g) was suspended in water (1300 mL) and methanesulfonic acid (115.4 g) was added to this mixture. The mixture was cooled to 10° C. and a solution of sodium nitrite (34.46 g) in water (200 mL) was added at a rate such that the temperature stayed below 12° C. The mixture was stirred for 30 min and added to an ice-cold solution of salicylic acid (69.65 g), sodium hydroxide (40.35 g) and sodium carbonate (106.9 g) in 1 L water at 7-12° C. After 3 hours at 10° C., the mixture was heated to 60-65° C. and acidified to pH 4.0-4.5 by the addition of hydrochloric acid. After a further 3 hours at 60-65° C., the mixture was cooled to ambient temperature, filtered, washed with water and dried in vacuo to yield Balsalazide. Yield ca. 90%. Balsalazide was transformed into its disodium salt in ca. 85% yield by treatment with aqueous NaOH solution followed by crystallization from n-propanol/methanol.

1H-NMR (400 MHz; D2O): δ=8.04 ppm (s); 7.67 ppm (d; J=8.2 Hz); 7.62 ppm (d, J=9.2 Hz); 7.53 ppm (d; J=8.2 Hz); 6.84 ppm (d; J=8.9 Hz); 3.57 ppm (t, J=7.1 Hz); 2.53 ppm (t; J=7.2 Hz).

Example 2 Continuous Process

For the continuous operation, a conventional dual-head metering pump (Ratiomatic by FMI) was used to deliver the mesylate solution and the aqueous sodium nitrite solution. The schematic diagram shown in FIG. 4 represents a set-up used for the continuous process. The first pump-head was set at 13.9 g/min whereas the second was set at 2.1 g/min. These flow rates offered a residence time of 9.4 min. The yield of the coupled intermediate from this residence time was 93%. The working solutions were prepared as follow:

The mesylate solution was prepared by the addition into a 2 L 3-necked round bottom flask, of N-(4-aminobenzoyl) β-alanine (120 g) followed by of DI water (1560 g) and methanesulfonic acid (177.5 g) (Batch appearance: clear solution). The first pump-head was primed with this solution and the flow rate was adjusted to 13.9 g/min.

The sodium nitrite solution was prepared by dissolving of sodium nitrite (41.8 g) in of DI water (240 g) (Batch appearance: clear solution). The second pump-head was primed with this solution and the flow rate adjusted to 2.1 g/min.

The quenching solution (sodium salicylate) was made by adding salicylic acid (139.3 g) to DI water (900 g) followed by of sodium carbonate (106.9 g) and 50% aqueous sodium hydroxide (80 g).

The diazotation reaction was performed in a 500 ml jacketed flow reactor with a bottom drain valve. The drain valve was set at 16 g/min. For reactor start-up, the flow reactor was charged with 150 mL of DI water as a working volume and cooled to the reactions initial temperature of 0-5° C. Concomitantly, the additions of the mesylate and sodium nitrite solutions were started and the bottom valve of the flow reactor was opened. During the diazotization, the flow rate of both solutions remained fixed and the temperature was kept below 12° C. and at the end of additions the pumps were stopped while the remaining contents in the flow reactor were drained into the quenching salicylic acid solution. Analysis of the contents in the quenching reactor indicated no signs of uncoupled starting material (diazonium compound). The reactor contents were heated to 60-65° C. for 2-3 hrs before adjusting the pH to precipitate the coupling product. This provided 191.5 g of product.

Cited Patent Filing date Publication date Applicant Title
US4412992 Jul 8, 1981 Nov 1, 1983 Biorex Laboratories Limited 2-Hydroxy-5-phenylazobenzoic acid derivatives and method of treating ulcerative colitis therewith
US6458776 * Aug 29, 2001 Oct 1, 2002 Nobex Corporation 5-ASA derivatives having anti-inflammatory and antibiotic activity and methods of treating diseases therewith
1 Chai, et al., Huaxi Yaoxue Zazhi, Jiangsu Institute of Materia Medica, Nanjing, China, 2004, 19(6), 431-433.
2 Shan, et al., Zhongguo Yaowu Huaxue Zazhi, Institute of Materia Medica, Peking Union Medical College, Beijing China, 2001, 11(2), 110-111.
3 Shi, et al., Zhongguo Yiyao Gongya Zazhi, Shanghai Institute of Pharmaceutical Industry, Shanghai, China, 2003, 34(11), 537-538.
4 Su, et al., Huaxue Gongye Yu Gongcheng (Tianjin, China), College of Chemistry and Chemical Eng., Donghua Univ., Shanghai, China, 2005, 22(4), 313-315.
5 Ullrich, et al., Decomposition of aromataic diazonium compounds, Thermochimica Acta, 1993, 225, 201-211.


  • Prakash, A; Spencer, CM: Drugs (DRUGAY) 1998 56 83- 89.
  • DE 3128819 (Biorex the Lab .; appl 07/21/1981;. GB -prior 07/21/1980, 07.07.1981.).


  1. Jump up^ Kruis, W.; Schreiber, I.; Theuer, D.; Brandes, J. W.; Schütz, E.; Howaldt, S.; Krakamp, B.; Hämling, J.; Mönnikes, H.; Koop, I.; Stolte, M.; Pallant, D.; Ewald, U. (2001). “Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses”. Gut. 49 (6): 783–789. doi:10.1136/gut.49.6.783. PMC 1728533Freely accessible. PMID 11709512.
1 to 5 of 5
Patent ID Patent Title Submitted Date Granted Date
US8232265 Multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients 2007-04-26 2012-07-31
US2007213304 Use of Aminosalicylates in Diarrhoea-Predominent Irritable Bowel Syndrome 2007-09-13
US7119079 Bioadhesive pharmaceutical compositions 2004-07-22 2006-10-10
US6699848 Bioadhesive anti-inflammatory pharmaceutical compositions 2004-03-02
Balsalazide structure.svg
Clinical data
Trade names Colazal, Giazo
AHFS/ Monograph
MedlinePlus a699052
  • US: B (No risk in non-human studies)
ATC code A07EC04 (WHO)
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability <1%
Protein binding ≥99%
Biological half-life 12hr
CAS Number 80573-04-2 Yes
PubChem (CID) 5362070
DrugBank DB01014 Yes
ChemSpider 10662422 Yes
ChEBI CHEBI:267413 Yes
ECHA InfoCard 100.117.186
Chemical and physical data
Formula C17H15N3O6
Molar mass 357.318 g/mol
3D model (Jmol) Interactive image


Title: Balsalazide
CAS Registry Number: 80573-04-2
CAS Name: 5-[(1E)-[4-[[(2-Carboxyethyl)amino]carbonyl]phenyl]azo]-2-hydroxybenzoic acid
Additional Names: (E)-5-[[p-[(2-carboxyethyl)carbamoyl]phenyl]azo]-2-salicylic acid
Molecular Formula: C17H15N3O6
Molecular Weight: 357.32
Percent Composition: C 57.14%, H 4.23%, N 11.76%, O 26.87%
Literature References: Analog of sulfasalazine, q.v. Prodrug of 5-aminosalicylic acid where carrier molecule is 4-aminobenzoyl-b-alanine. Prepn: R. P. K. Chan, GB 2080796; idem, US 4412992 (1982, 1983 both to Biorex). Toxicology study and clinical metabolism: idem et al., Dig. Dis. Sci. 28, 609 (1983). Review of pharmacology and clinical efficacy in ulcerative colitis: A. Prakash, C. M. Spencer, Drugs 56, 83 (1998).
Properties: Crystals from hot ethanol, mp 254-255°.
Melting point: mp 254-255°
Derivative Type: Disodium salt dihydrate
CAS Registry Number: 150399-21-6; 82101-18-6 (anhydrous)
Manufacturers’ Codes: BX-661A
Trademarks: Colazal (Salix); Colazide (Shire)
Molecular Formula: C17H13N3Na2O6.2H2O
Molecular Weight: 437.31
Percent Composition: C 46.69%, H 3.92%, N 9.61%, Na 10.51%, O 29.27%
Properties: Orange to yellow microcrystalline powder, mp >350°. Nonhygroscopic. Freely sol in water, isotonic saline; sparingly sol in methanol, ethanol. Practically insol in organic solvents.
Melting point: mp >350°
Therap-Cat: Anti-inflammatory (gastrointestinal).
Keywords: Anti-inflammatory (Gastrointestinal); Anti-inflammatory (Nonsteroidal); Salicylic Acid Derivatives.




P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Happy New Year's Eve from Google!

Glenmark Launches First and Only Generic Version of Zetia® (Ezetimibe) in the United States

Glenmark launches generic version of Zetia in US

Illustration Image Courtesy…

“We have launched ezetimibe, the first and only generic version of Zetia (Merck) in the United States for the treatment of high cholesterol,”……….



Glenmark Launches First and Only Generic Version of Zetia® in the United States 

Mumbai, India; December 12, 2016: Glenmark Pharmaceuticals Inc., USA today announced the availability of ezetimibe, the first and only generic version of ZETIA® (Merck) in the United States for the treatment of high cholesterol. The availability of ezetimibe is the result of a licensing partnership with Par Pharmaceutical, an Endo International plc operating company, with whom Glenmark will share profits. Glenmark and its partner, Endo will be entitled to 180 days of generic drug exclusivity for ezetimibe as provided for under section 505(j)(5)(B)(iv) of the FD&C Act.

Ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-
C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) in patients with primary
(heterozygous familial and non-familial) hyperlipidemia.
According to IMS Health data for the 12-month period ending October 2016, annual U.S. sales of Zetia®
10 mg were approximately $2.3 billion.
“Glenmark has a deep heritage of bringing safe, effective and affordable medicines to patients around
the world,” said Robert Matsuk, President of North America and Global API at Glenmark
Pharmaceuticals Ltd. “Our partnership with Par to bring the first generic version of ZETIA® to market
only underscores our joint commitment to bridging the gap between patients and the medicines they
need most.”
“We, along with our partners at Glenmark, are proud to be able to offer patients managing their
cholesterol levels the first generic version of ZETIA®,” said Tony Pera, President of Par Pharmaceutical.
“Par remains committed to providing patients access to high quality and affordable medicines.”
Glenmark’s current portfolio consists of 111 products authorized for distribution in the U.S. marketplace
and 64 ANDA’s pending approval with the U.S. Food and Drug Administration. In addition to these
internal filings, Glenmark continues to identify and explore external development partnerships to
supplement and accelerate the growth of its existing pipeline and portfolio.

About Glenmark Pharmaceuticals Ltd.:
Glenmark Pharmaceuticals Ltd. (GPL) is a research-driven, global, integrated pharmaceutical organization headquartered at Mumbai, India. It is ranked among the top 80 Pharma & Biotech companies of the world in terms of revenue (SCRIP 100 Rankings published in the year 2016). Glenmark is a leading player in the discovery of new molecules both NCEs (new chemical entity) and NBEs (new biological entity). Glenmark has several molecules in various stages of clinical development and is primarily focused in the areas of Inflammation [asthma/COPD, rheumatoid arthritis etc.] and Pain [neuropathic pain and inflammatory pain]. The company has a significant presence in the branded generics markets across emerging economies including India. GPL along with its subsidiaries operate 17 manufacturing facilities across four countries and has five R&D centers. The Generics business of Glenmark services the requirements of the US and Western European markets. The API business sells its products in over 80 countries including the US, EU, South America and India………

About Endo International plc:
Endo International plc (NASDAQ / TSX: ENDP) is a global specialty pharmaceutical company focused on improving patients’ lives while creating shareholder value. Endo develops, manufactures, markets and distributes quality branded and generic pharmaceutical products as well as over-the-counter medications though its operating companies. Endo has global headquarters in Dublin, Ireland, and U.S. headquarters in Malvern, PA. Learn more at


Dec 08, 2016, 08.16 PM | Source: CNBC-TV18 Glenmark to launch cholesterol drug Zetia in US on Dec 12 Glenmark was the first to file for the generic version of Zetia and it means that after the launch on December 12, only Glenmark and Merck will sell generic Zetia in the US market for the next 6 months. Glenmark   is launching cholesterol drug Zetia with 6 months exclusivity in the US on December 12. The company has partnered with Par Pharma on the drug and has a 50:50 profit sharing agreement with Par on Zetia. Glenmark was the first to file for the generic version of Zetia and it means that after the launch on December 12, only Glenmark and Merck will sell generic Zetia in the US market for the next 6 months. Total revenue estimated to be generated is around USD 400-500 million and post profit sharing with Par, Glenmark should make around USD 200-250 million.

Read more at:

////////////Glenmark,  Launches,  First,  Only,  Generic Version,  Zetia®,  United States, ezetimibe, par pharmaceutical, cholesterol, Endo International plc

Зопиклон , Zopiclone, زوبيكلون , 佐匹克隆

Zopiclone structure.svg


1-Piperazinecarboxylic acid, 4-methyl-, 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester
256-138-9 [EINECS]
43200-80-2 [RN]

Structural formula

UV- Spectrum

Conditions : Concentration – 1 mg / 100 ml
The solvent designation schedule methanol 


0.1М HCl

0.1M NaOH

maximum absorption There 


303 nm 304 nm 277 nm 

237 nm

362 364 199


e 10500 10500 5800


IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

MASS spectrum

10 largest peaks:
Peak 42 56 99 112 139 143 217 245 246 247
Value 155 231 280 283 209 999 279 719 156 250


  • UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV

  • NIST/EPA/NIH Mass Spectral Library 2008

  • Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.

  • Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Brief background information

Salt ATC formula MM CASE
N05CF01 17 H 17 ClN 6 O 3 388.82 g / mol 43200-80-2


  • sedative

  • hypnotic

Classes substance

  • chlorine compounds

    • oxo

      • Esters of 1-piperazinecarboxylate

        • pyridines

          • Pirrolo [3,4-b] piraziny

Synthesis Way

Синтез a)

Trade names

country Tradename Manufacturer
Germany Optydorm DOLORGIET
Somnosan Hormos
Ksimovan Sanofi-Aventis
Zopi-cigar Actavis
various generic drugs
France imovane SanofiAventis
Noktireks Sanofi-Synthélabo
United Kingdom Snowman SanofiAventis
Italy imovane SanofiAventis
tion THERE
Japan Amoʙan Sanofi-Aventis; Chugai; Mitsubishi
Ukraine imovane Sanofi Winthrop Indastria, France
various generic drugs


  • coated tablets 7.5 mg;

  • Tablets 7.5 mg, 10 mg


  • DOS 2 300 491 (Rhône-Poulenc; appl. 5.1.1973; F-prior. 7.1.1972, 9.9.1972).

  • US 3 862 149 (Rhône-Poulenc; 21.1.1975; F-prior. 7.1.1972, 9.9.1972).

Two major zopiclone metabolites.

Two major zopiclone metabolites.

CAS Registry No.: 43200-80-2
Molecular Formula: C17H17ClN6O3 Molecular Weight: 388.8
Compound Name:

1-piperazinecarboxylic acid, 4-methyl-, 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo(3,4-b)pyrazin-5-yl ester

4-methyl-1-piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo(3,4-b)-pyrazin-5-yl ester

4-methyl-1-piperazinecarboxylic acid-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo(3,4-b)-pyrazin-5-yl ester

6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxo-5H-pyrrolo(3,4-b)pyrazin-5-yl 4-methyl-1-piperazinecarboxylate


6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazin-5-yl 4-methylpiperazine-1-carboxylate

amoban (R)


Zopiclone (Imovance), 4-methyl-1-piperzinecarboxylic acid 6-(5-chloro-2- pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester (Figure 1) is one of the non benzodiazepine sedative-hypnotics of the cyclopyrrolone class, sold by Rhone-Poulene Company in France since 1987. Although structurally unrelated to benzodiazepines, its pharmacological profile is similar, exhibiting sedative-hypnotic, anxiolytic, myorelaxant, and anticonvulsant activity.[1] Other than the first generation barbiturates and the second-generation benzodiazepines, zopiclone, which is widely used in Europe as well as other regions worldwide,[2,3] as a representative of the third generation sedative-hypnotic drugs, has been shown to be free from residual effects on performance and psychological function the day after intake and from the risks of accumulation because of its short elimination half-life (3.5 to 6.5 hours).[3,4] It is indicated for the short term treatment of insomnia, transient, situational or chronic insomnia, and insomnia secondary to psychiatric disturbances.[3]

REFERENCES 1. Mann, K.; Bauer, H.; Hiemke, C.; Ro¨schke, J.; Wetzel, H.; Benkert, O. Acute, subchronic and discontinuation effects of zopiclone on sleep EEG and nocturnal melatonin secretion. Eur. Neuropsychopharm. 1996, 6 (3), 163– 168. Structure Elucidation of Sedative-Hypnotic Zopiclone 359 Downloaded by [Dalhousie University] at 22:10 19 December 2012

2. Le´ger, D.; Janus, C.; Pellois, A.; Quera-Salva, M.A.; Dreyfus, J.P. Sleep, morning alertness and quality of life in subjects treated with zopiclone and in good sleepers. study comparing 167 patients and 381 good sleepers. Eur. Psychiat. 1995, 10 (973) Suppl. 3, 99s – 102s.

3. Piperaki, S.; Parissi-Poulou, M. Enantiomeric separation of zopiclone, its metabolites and products of degradation on a b-cyclodextrin bonded phase. J. Chromatogr. A 1996, 729 (1 – 2), 19 – 28

Spectral Data Analyses and Structure Elucidation of Sedative‐Hypnotic Zopiclone

Pages 349-360 | Received 10 Sep 2006, Accepted 18 Oct 2006, Published online: 13 Oct 2010

Zopiclone structure.svg
Zopiclone ball-and-stick.png
Systematic (IUPAC) name

(RS)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate

Clinical data
Trade names Imovane, Zimovane
AHFS/ International Drug Names
  • AU: C
  • US: C (Risk not ruled out)
Routes of
Oral tablets, 3.75 mg (UK), 5 or 7.5 mg
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: Class C (POM)
  • US: Schedule IV
Pharmacokinetic data
Bioavailability 75-80%[1]
Protein binding 52–59%
Metabolism Hepatic through CYP3A4and CYP2E1
Biological half-life ~5 hours (3.5–6.5 hours)

~7–9 hours for over 65

Excretion Urine (80%)
CAS Number 43200-80-2 Yes
ATC code N05CF01 (WHO)
PubChem CID 5735
DrugBank DB01198 Yes
ChemSpider 5533 Yes
KEGG D01372 Yes
ChEBI CHEBI:32315 Yes
Chemical data
Formula C17H17ClN6O3
Molar mass 388.808 g/mol
3D model (Jmol) Interactive image


MICONAZOLE NITRATE , Миконазол , ミコナゾール硝酸塩

Miconazole            C18H14Cl4N2O    416.13             [22916478]

Miconazole Nitrate            C18H14Cl4N2O.HNO3              479.14             [22832877]

ミコナゾール硝酸塩 JP16
Miconazole Nitrate

C18H14Cl4N2O▪HNO3 : 479.14








click on above image for clear view



1D 1H, n/a spectrum for Miconazole


2D [1H,1H]-TOCSY, n/a spectrum for Miconazole


1D DEPT90, n/a spectrum for Miconazole

1D DEPT135

1D DEPT135, n/a spectrum for Miconazole


2D [1H,13C]-HSQC

2D [1H,13C]-HSQC, n/a spectrum for Miconazole

2D [1H,13C]-HMBC

2D [1H,13C]-HMBC, n/a spectrum for Miconazole

2D [1H,1H]-COSY

2D [1H,1H]-COSY, n/a spectrum for Miconazole

2D [1H,13C]-HMQC

2D [1H,13C]-HMQC, n/a spectrum for Miconazole
Miconazole is an imidazole antifungal agent, developed by Janssen Pharmaceutica, commonly applied topically to the skin or tomucous membranes to cure fungal infections. It works by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes. It can also be used against certain species of Leishmania protozoa which are a type of unicellular parasites that also contain ergosterol in their cell membranes. In addition to its antifungal and antiparasitic actions, it also has some antibacterialproperties. It is marketed in various formulations under various brand names.

Miconazole is also used in Ektachrome film developing in the final rinse of the Kodak E-6 process and similar Fuji CR-56 process, replacing formaldehydeFuji Hunt also includes miconazole as a final rinse additive in their formulation of the C-41RA rapid access color negative developing process.
It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.[1]

ALTERNATIVE ROUTES beginning with the racemic raw material will likely be more costly or more time-consuming to develop, Cox says. Crystallization might be tricky because the stereogenic center does not have a group that can readily undergo acid-base chemistry. Catalytic asymmetric chemistry will necessitate converting the raw material to an appropriate substrate and identifying effective, as well as usable, chemical catalysts or biocatalysts.
What happens to the unwanted enantiomer also depends on the economics. Reracemizing and feeding the racemate back into the process is ideal but not always practical. In the miconazole case, the raw material costs $32 per kg. It is unlikely that reracemizing would be less costly in this example, Cox explains.
People should not forget that the goal of chiral technologies–enantiopure product–also may be achieved with chemistry that already exists, notes David R. Dodds, founder of Dodds & Associates LLC, Manlius, N.Y., a consulting service for biotechnology and chemical companies. Process chemists seek the most robust, most productive, and least expensive synthetic route and aim to find it as fast as possible. Any reaction that can help reach this goal is useful. It is the overall process cost that will dictate which reactions will be used. And that cost covers not only reagents but also waste streams, utilities, equipment use, unit operations, and downstream requirements. Thus, it may be more commercially attractive to replace an elegant but expensive single reaction with several more mundane ones that have a lower total cost, he says. Such a situation is likely to arise when an asymmetric step requires an expensive chiral catalyst or chiral auxiliary.

Brief background information


Salt ATC Formula MM CAS
18 H 14 Cl 4 N 2 O 416.14 g / mol 22916-47-8
mononitrate A01AB09 
18 H 14 Cl 4 N 2 O ⋅ HNO 3 479.15 g / mol 22832-87-7



  • antifungal agent for topical use
  • antimycotic agent

Classes substance


  • Imidazoles, 1- (hlorfenetil) imidazoles

synthesis Way


Synthesis of a)

trade names


A country Tradename Manufacturer
Germany Castellani Hollborn
Daktar McNeil
Derma-Mikotral Rosen Pharma
Fungur HEXAL
Gyno-Daktar Janssen-Cilag, 1974
Gyno-Mikotral Rosen Pharma
Infektozoor Mundgel Infectopharm
Mikobeta betapharm
Mikotar Dermapharm
Mikoderm Engelhard
Mikotin Ardeypharm
Vobamik Almirall Hermal
France Daktapin Janssen-Cilag
Gyno-Daktapin Janssen-Cilag
Loramik Bioalliance
United Kingdom Gyno-Daktapin Janssen-Cilag
Italy Daktapin Janssen-Cilag
Mikonal Ecobi
Mikotef LPB
Miderm Mendelejeff
Nizakol PS Pharma
Pivanazolo Medestea
Prilagin Sofar
Japan Florid Mochida
USA Fungoid Pedinol
Ukraine GІNEZOL 7 Sagmel, Іnk., USA
MІKONAZOL-Darnitsa CJSC “Farmatsevtichna FIRMA” Darnitsa “, m. Kyiv, Ukraine
MІKOGEL BAT “Kiїvmedpreparat”, m. Kyiv, Ukraine
various generic drugs



  • ampoule 200 mg / 20 ml;
  • cream 1%, 2 g / 100 g 20 mg / g;
  • losyon 1%;
  • ointment 1%;
  • 2% oral gel;
  • Powder 2 g / 100 g 20 mg / g (in the form mononitrate);
  • solution of 20 mg / ml;
  • 100 mg suppositories;
  • Tablets of 250 mg (free base form);
  • vaginal cream 20 mg / g;
  • bottles of 400 mg / 40 ml



  1. Synthesis of a)
    • DAS 1,940,388 (Janssen; appl 8.8.1969;. USA-prior 19.8.1968, 23.7.1969.).
    • US 3,717,655 (Janssen; 20.2.1973; appl 19.8.1968.).
    • US 3,839,574 (Janssen; 1.10.1974; prior 23.7.1969.).

Miconazole nitrate was prepared by Godefori et
7]. Imidazole 1 was coupled with
brominated 2,4‑dichloroacetophenone 2 and the resulting ketonic product 3
was reduced with sodium borohydride to its corresponding alcohol 4. The
latter compound 4 was then coupled with 2,4-dichlorotoluene by sodium borohydride
in hexamethylphosphoramide (an aprotic solvent) which was then extracted with
nitric acid to give miconazole nitrate.



2-     Miconazole was also
prepared by Molina Caprile [8] as follows:
Phenyl methyl ketone 1 was brominated to give
1-phenyl-2-bromoethanone 2. Compound 2 was treated with
methylsulfonic acid to yield the corresponding methylsulfonate 3.
Etherification of 3 gave the a‑benzyloxy derivative 4 and compound 4 was
then chlorinated to give the 2,4‑dichlorinated derivative in both aromatic ring
systems 5. Compound 5 reacted with imidazole in dimethylformamide
to give miconazole 6 [7] which is converted to miconazole nitrate.


3-     Ye
et al reported that the reduction of 2,4-dichlorophenyl-2-chloroethanone
1 with potassium borohydride in dimethylformamide to give 90% a‑chloromethyl-2,4-dichlorobenzyl
alcohol 2. Alkylation of imidazole with compound 2 in dimethyl­formamide
in the presence of sodium hydroxide and triethylbenzyl ammonium chloride, gave
1-(2,4‑dichlorophenyl-2-imidazolyl)ethanol 3 and etherification of 3
with 2,4-dichlorobenzyl chloride under the same condition, 62% yield of
miconazole [9].
4-     Liao
and Li enantioselectively synthesized and studied the antifungal activity of
optically active miconazole and econazole. The key step was the
enantioselective reduction of 2‑chloro-1-(2,4-dichlorophenyl)ethanone catalyzed
by chiral oxazaborolidine [10].
5-     Yanez
et al reported the synthesiz of miconazole and analogs through a
carbenoid intermediate. The process involves the intermolecular insertion of
carbenoid species to imidazole from a‑diazoketones with copper acetylacetonate as the key
reaction of the synthetic route [11].
5-11 as 1-7
1.             E.F. Godefori and J. Heeres, Ger. Pat. 1,940,388
E.F. Godefori and J. Heeres, U.S. Pat. 3,717,655
E.F. Godefori, J. Heeres, J. van Cutsem and P.A.J.
Janssen, J. Med. Chem., 12, 784 (1969).
F. Molina Caprile, Spanish Patent ES 510870 A1
B. Ye, K. Yu and Q. Huang, Zhongguo Yiyao Gongye
, 21, 56 (1990).
Y.W. Liao and H.X. Li, Yaoxue Xuebao, 28,
22 (1993).
E.C. Yanez, A.C. Sanchez, J.M.S. Becerra, J.M.
Muchowski and C.R. Almanza, Revista de la Sociedad Quimica de Mexico, 48,
49 (2004).

MiconazoleTitle: Miconazole

CAS Registry Number: 22916-47-8
CAS Name: 1-[2-(2,4-Dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole
Additional Names: 1-[2,4-dichloro-b-[(2,4-dichlorobenzyl)oxy]phenethyl]imidazole
Molecular Formula: C18H14Cl4N2O
Molecular Weight: 416.13
Percent Composition: C 51.95%, H 3.39%, Cl 34.08%, N 6.73%, O 3.84%
Literature References: Prepn: E. F. Godefroi et al., J. Med. Chem. 12, 784 (1969); E. F. Godefroi, J. Heeres, DE 1940388;eidem, US 3717655 (1970, 1973 to Janssen). Clinical evaluation: Brugmans et al., Arch. Dermatol. 102, 428 (1970); Godts et al.,Arzneim.-Forsch. 21, 256 (1971). Review: P. Janssen, W. Van Bever, in Pharmacological and Biochemical Properties of Drug Substances vol. 2, M. E. Goldberg, Ed. (Am. Pharm. Assoc., Washington, DC, 1979) pp 333-354; R. C. Heel et al., Drugs 19, 7-30 (1980).
Derivative Type: Nitrate
CAS Registry Number: 22832-87-7
Manufacturers’ Codes: R-14889
Trademarks: Aflorix (Gramon); Albistat (Ortho); Andergin (ISOM); Brentan (Janssen); Conoderm (C-Vet); Conofite (Mallinckrodt); Daktar (Janssen); Daktarin (Janssen); Deralbine (Andromaco); Dermonistat (Ortho); Epi-Monistat (Cilag); Florid (Mochida); Fungiderm (Janssen); Fungisdin (Isdin); Gyno-Daktarin (Janssen); Gyno-Monistat (Cilag-Chemie); Micatin (J & J); Miconal Ecobi (Ecobi); Micotef (LPB); Monistat (Cilag-Chemie); Prilagin (Gambar); Vodol (Andromaco)
Molecular Formula: C18H14Cl4N2O.HNO3
Molecular Weight: 479.14
Percent Composition: C 45.12%, H 3.16%, Cl 29.60%, N 8.77%, O 13.36%
Properties: Crystals, mp 170.5° (Godefroi, Heeres, 1970); 184-185° (Godefroi).
Melting point: mp 170.5° (Godefroi, Heeres, 1970); 184-185° (Godefroi)
Derivative Type: (+)-Form nitrate
Properties: mp 135.3°. [a]D20 +59° (methanol).
Melting point: mp 135.3°
Optical Rotation: [a]D20 +59° (methanol)
Derivative Type: (-)-Form nitrate
Properties: mp 135°. [a]D20 -58° (methanol).
Melting point: mp 135°
Optical Rotation: [a]D20 -58° (methanol)
Therap-Cat: Antifungal (topical).
Therap-Cat-Vet: Antifungal (topical).
Keywords: Antifungal (Synthetic); Imidazoles.


  1. Jump up^ “WHO Model List of EssentialMedicines” (PDF)World Health Organization. October 2013. Retrieved 22 April 2014.
  2. Jump up^ British National Formulary ’45’ March 2003
  3. Jump up^ “Strange Beauty: Monistat Effectively Increases Hair Growth?”. Black Girl With Long Hair. Retrieved 12 April 2012.
  4. Jump up^ Ju, Jiang; Tsuboi, Ryoji; Kojima, Yuko; Ogawa, Hideoki (2005). “Topical application of ketoconazole stimulates hair growth in C3H/HeN mice”Journal of dermatology32: 243–247.
  5. Jump up^ S., Venturoli; O. Marescalchi; F. M. Colombo; S. Macrelli; B. Ravaioli; A. Bagnoli; R. Paradisi; C. Flamigni (April 1999). “A Prospective Randomized Trial Comparing Low Dose Flutamide, Finasteride, Ketoconazole, and Cyproterone Acetate-Estrogen Regimens in the Treatment of Hirsutism”The Journal of Clinical Endocrinology and Metabolism84 (4): 1304–1310. doi:10.1210/jc.84.4.1304. Retrieved 12 April 2012.
  6. Jump up^ Duret C, Daujat-Chavanieu M, Pascussi JM, Pichard-Garcia L, Balaguer P, Fabre JM, Vilarem MJ, Maurel P, Gerbal-Chaloin S (2006). “Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor”. Mol. Pharmacol70 (1): 329–39. doi:10.1124/mol.105.022046PMID 16608920.
  7. Jump up^ Najm, Fadi J.; Madhavan, Mayur; Zaremba, Anita; Shick, Elizabeth; Karl, Robert T.; Factor, Daniel C.; Miller, Tyler E.; Nevin, Zachary S.; Kantor, Christopher (2015-01-01).“Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo”Nature522 (7555). doi:10.1038/nature14335.
  8. Jump up^ United States Patent 5461068

External links




Miconazole ball-and-stick.png
Systematic (IUPAC) name
Clinical data
Trade names Desenex, Monistat, Zeasorb-AF
AHFS/ Monograph
MedlinePlus a601203
  • AU: A
  • US: C (Risk not ruled out)
  • In Australia, it is category A when used topically. In the US, the pregnancy category is C for oral and topical treatment.
Routes of
Legal status
Legal status
  • AU: S2 (Pharmacy only)
  • UK: POM (Prescription only)
  • US: OTC
  • Schedule 2 in Australia for topical formulations, schedule 3 (Aus) for vaginal use and for oral candidiasis, otherwise schedule 4 in Australia
Pharmacokinetic data
Bioavailability n/a
Metabolism n/a
Biological half-life n/a
Excretion n/a
CAS Number 22916-47-8 Yes
ATC code A01AB09 (WHO)A07AC01 (WHO)D01AC02 (WHO)G01AF04 (WHO)J02AB01 (WHO)S02AA13 (WHO)
PubChem CID 4189
DrugBank DB01110 Yes
ChemSpider 4044 Yes
KEGG D00416 Yes
ChEBI CHEBI:6923 Yes
Chemical data
Formula C18H14Cl4N2O
Molar mass 416.127 g/mol
Chirality Racemic mixture

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Arformoterol, (R,R)-Formoterol For Chronic obstructive pulmonary disease (COPD)



  • MF C19H24N2O4
  • MW 344.405
Cas 67346-49-0
Chronic obstructive pulmonary disease (COPD)
  • Sunovion/Sepracor (Originator)
  • Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists
  • LAUNCHED 2007 , Phase III ASTHMA
Formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-

Arformoterol is a long-acting β2 adrenoreceptor agonist (LABA) indicated for the treatment of chronic obstructive pulmonary disease(COPD). It is sold by Sunovion, under the trade name Brovana, as a solution of arformoterol tartrate to be administered twice daily (morning and evening) by nebulization.[1]

Arformoterol inhalation solution, a long-acting beta2-adrenoceptor agonist, was launched in the U.S. in 2007 for the long-term twice-daily (morning and evening) treatment of bronchospasm in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. The product, known as Brovana(TM), for use by nebulization only, is the first long-acting beta2-agonist to be approved as an inhalation solution for use with a nebulizer. The product was developed and is being commercialized by Sunovion Pharmaceuticals (formerly Sepracor)


It is the active (R,R)-(−)-enantiomer of formoterol and was approved by the United States Food and Drug Administration (FDA) on October 6, 2006 for the treatment of COPD.

Arformoterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. Arformoterol inhalation is used to prevent bronchoconstriction in people with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. The use of arformoterol is pending revision due to safety concerns in regards to an increased risk of severe exacerbation of asthma symptoms, leading to hospitalization as well as death in some patients using long acting beta agonists for the treatment of asthma.

Arformoterol is an ADRENERGIC BETA-2 RECEPTOR AGONIST with a prolonged duration of action. It is used to manage ASTHMA and in the treatment of CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

Arformoterol is a beta2-Adrenergic Agonist. The mechanism of action of arformoterol is as an Adrenergic beta2-Agonist.
Arformoterol is a long-acting beta-2 adrenergic agonist and isomer of formoterol with bronchodilator activity. Arformoterol selectively binds to and activates beta-2 adrenergic receptors in bronchiolar smooth muscle, thereby causing stimulation of adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cAMP). Increased intracellular cAMP levels cause relaxation of bronchial smooth muscle and lead to a reduced release of inflammatory mediators from mast cells. This may eventually lead to an improvement of airway function.

Arformoterol tartrate

  • Molecular FormulaC23H30N2O10
  • Average mass494.492
  •  cas 200815-49-2
  • 183-185°C
Butanedioic acid, 2,3-dihydroxy-, (2R,3R)-, compd. with formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]- (1:1) [ACD/Index Name]
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl]phenyl}formamide 2,3-dihydroxybutanedioate (salt)
N-[2-Hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (+)-(2R,3R)-Tartaric Acid; (-)-Formoterol 1,2-Dihydroxyethane-1,2-dicarboxylic Acid; (R,R)-Formoterol Threaric Acid; Arformoterol d-Tartaric Acid; Arformoterol d-α,β-Dihydroxysuccinic Acid
200815-49-2 CAS
Arformoterol tartrate (USAN)
Arformoterol Tartrate, can be used in the synthesis of Omeprazole (O635000), which is a proton pump inhibitor, that inhibits gasteric secretion, also used in the treatment of dyspepsia, peptic ulcer disease, etc. Itis also the impurity of Esomeprazole Magnesium (E668300), which is the S-form of Omeprazole, and is a gastric proton-pump inhibitor. Also, It can be used for the preparation of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy.




Example 1

Synthesis of (R,R)-Formoterol-L-tartrate Form D

A solution containing 3.9 g (26 mmol) of L-tartaric acid and 36 mL of methanol was added to a solution of 9 g (26 mmol) of arformoterol base and 144 mL methanol at C. Afterwards, the resulting mixture was seeded with form D and stirred at C. for 1 hour. It was then further cooled to C. for 1 hour and the product collected by filtration and dried under inlet air (atmospheric pressure) for 16 hours to provide 11.1 g (86% yield) (99.7% chemical purity, containing 0.14% of the degradation impurity (R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy- l]amino]ethanol) of (R,R)-formoterol L-tartrate form D, as an off white powder. .sup.1H-NMR (200 MHz, d.sub.6-DMSO) .delta.: 1.03 (d, 3H); 2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H); 6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH). No residual solvent was detected (.sup.1H-NMR).

PSD: d.sub.50=2.3 .mu.m.

Tetrahedron Letters, Vol. 38, No. 7, pp. 1125-1128, 1997
Enantio- and Diastereoselective Synthesis of all Four Stereoisomers of Formoterol

Taking Advantage of Polymorphism To Effect an Impurity Removal:  Development of a Thermodynamic Crystal Form of (R,R)-FormoterolTartrate

Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.
Org. Proc. Res. Dev., 2002, 6 (6), pp 855–862
DOI: 10.1021/op025531h


Abstract Image

The development and large-scale implementation of a novel technology utilizing polymorphic interconversion and crystalline intermediate formation of (R,R)-formoterol l-tartrate ((R,R)-FmTA, 1) as a tool for the removal of impurities from the final product and generation of the most thermodynamically stable crystal form is reported. The crude product was generated by precipitation of the free base as the l-tartrate salt in a unique polymorphic form, form B. Warming the resultant slurry effected the formation of a partially hydrated stable crystalline intermediate, form C, with a concomitant decrease in the impurity levels in the solid. Isolation and recrystallization of form C provided 1 in the thermodynamically most stable polymorph, form A.

 SYN 4


Formoterol, (+/-)N-[2-hydroxy-5-[1-hydroxy-2-[[2-(p-methoxyphenyl)-2-propylamino]ethyl]phenyl]-formamide, is a highly potent and β2-selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. Its chemical structure is depicted below:
Figure imgb0001
Formoterol has two chiral centres, each of which can exist into two different configurations. This results into four different combinations, (R,R), (S,S), (S,R) and (R,S). Formoterol is commercially available as a racemic mixture of 2 diasteromers (R,R) and (S,S) in a 1:1 ratio. The generic name Formoterol always refers to its racemic mixture. Trofast et al. (Chirality, 1, 443, 1991) reported on the potency of these isomers, showing a decrease in the order of (R,R)>(R,S)≥(S,R)>(S,S). The (R,R) isomer, also known as Arformoterol, being 1000 fold more potent than the (S,S) isomer. Arformoterol is commercialised by Sepracor as Brovana
Formoterol was first disclosed in Japanese patent application (Application N° 13121 ) whereby Formoterol is synthesised by N-alkylation using a phenacyl bromide as described in the scheme below:
Figure imgb0002
Afterwards, a small number of methods have been reported so far, regarding the synthesis of the (R,R) isomer, also referred as (R,R)-Formoterol and Arformoterol.
Murase et al. [Chem. Pharm. Bull. 26(4) 1123-1129(1978)] reported the preparation of (R,R)-Formoterol from a racemic mixture of the (R,R) and (S,S) isomers by optical resolution using optically active tartaric acid. Trofast et al. described a method in which 4-benzyloxy-3-nitrostyrene oxide was coupled with a optically pure (R,R)- or (S,S)-N-phenylethyl-N-(1-p-methoxyphenyl)-2-(propyl)amine to give a diastereomeric mixture of Formoterol precursors. These precursors were further separated by HPLC in order to obtain pure Formoterol isomers. Both synthetic processes undergo long synthetic procedures and low yields.
Patent publication EP0938467 describes a method in which Arformoterol is prepared via the reaction of the optically pure (R) N-benzyl-2-(4-methoxyphenyl)-1-(methylethylamine) with an optically pure (R)-4-benzyloxy-3-nitrostyrene oxide or (R)-4-benzyloxy-3-formamidostyrene oxide followed by formylation of the amino group. This method requires relatively severe reaction conditions, 24 h at a temperature of from 110 up to 130 °C as well as a further purification step using tartaric acid in order to eliminate diastereomer impurities formed during the process.
WO2009/147383 discloses a process for the preparation of intermediates of Formoterol and Arformoterol which comprises a reduction of a ketone intermediate of formula:
Figure imgb0003
Using chiral reductive agent with an enantiomeric excess of about 98% which requires further purification steps to obtain a product of desired optical purity.
 R,R)-Formoterol (Arformoterol) or a salt thereof from optically pure and stable intermediate (R)-2-(4-Benzyloxy-3-nitro-phenyl)-oxirane (compound II), suitable for industrial use, in combination with optically pure amine in higher yields, as depicted in the scheme below:
Figure imgb0011

Compound (R, R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methylethyl]-(1-phenyl-ethyl)-amino]-ethanol (compound VI), having the configuration represented by the following formula:

Figure imgb0018

Examples(R)-2-(4-Benzyloxy-3-nitro-phenyl)-oxirane (II)

A solution of 90 g (0.25 mol) of (R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-bromo-ethanol (compound I) in 320 mL of toluene and 50 mL of MeOH was added to a stirred suspension of 46 g (0.33 mol) of K2CO3 in 130 mL of toluene and 130 mL of MeOH. The mixture was stirred at 40°C for 20 h and washed with water (400 mL). The organic phase was concentrated under reduced pressure to a volume of 100 mL and stirred at 25 °C for 30 min. It was then further cooled to 0-5°C for 30 min. and the product collected by filtration and dried at 40 °C to provide 67.1 g (97% yield) (98% chemical purity, 100% e.e.) of compound II as an off-white solid. 1 H-NMR (200 MHz, CDCl3) δ: 2.80-2.90 (m, 2H); 3.11-3.20 (m, 2H), 3.80-3.90 (m, 1H); 5.23 (s, 2H); 7.11 (d, 2H); 7.41 (m, 5H), 7.76 (d, 2H).

Preparation of (R,R)-[2-(4-Methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amine (III)

A solution of 13 g (78.6 mmol) of 1-(4-Methoxy-phenyl)-propan-2-one and 8.3 g (78.6 mmol) of (R)-1-Phenylethylamine in 60 mL MeOH was hydrogenated in the presence of 1.7 g of Pt/C 5% at 10 atm. and 30 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and concentrated under reduced pressure to give compound III as an oil. The obtained oil was dissolved in 175 mL of acetone, followed by addition of 6.7 mL (80.9 mmol) of a 12M HCl solution. The mixture was stirred at 23 °C for 30 min and at 0-5 °C for 30 min. The product collected by filtration and dried at 40 °C to provide 13.8 g of the hydrochloride derivate as a white solid. The obtained solid was stirred in 100 mL of acetone at 23 °C for 1h and at 0-5 °C for 30 min, collected by filtration and dried at 40 °C to provide 13.2 g of the hydrochloride derivate as a white solid. This compound was dissolved in 100 mL of water and 100 mL of toluene followed by addition of 54 mL (54 mmol) of 1N NaOH solution. The organic phase was concentrated to give 11.7 g (55% yield) (99% chemical purity and 100% e.e) of compound III as an oil.1H-NMR (200 MHz, CDCl3) δ: 0.88 (d, 3H); 1.31 (d, 3H), 2.40-2.50 (m, 1H); 2.60-2.80 (m, 2H); 3.74 (s, 3H); 3.90-4.10 (m, 1H); 6.77- 6.98 (m, 4H), 7.31 (s, 5H).

Synthesis of (R,R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (IV)

A 1-liter flask was charged with 50g (0.18 mol) of II and 50g (0.18 mol) of III and stirred under nitrogen atmosphere at 140 °C for 20 h. To the hot mixture was added 200 mL of toluene to obtain a solution, which was washed with 200 mL of 1N HCl and 200 mL of water. The organic phase was concentrated under reduced pressure to give 99 g (99% yield) (88% chemical purity) of compound IV as an oil. Enantiomeric purity 100%. 1H-NMR (200 MHz, CDCl3) δ: 0.98 (d, 3H); 1.41 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.74 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.19 (s, 2H); 6.69-7.42 (m, 16H); 7.77 (s, 1H).

Synthesis of (R, R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (V)

A solution of 99 g (0.18 mol) of IV in 270 mL IPA and 270 mL toluene was hydrogenated in the presence of 10 g of Ni-Raney at 18 atm and 40 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 87 g (92% yield) (83% chemical purity, 100 % e.e.) of compound V as an oil. 1H-NMR (200 MHz, CDCl3) δ: 0.97 (d, 3H); 1.44 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.74 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.07 (s, 2H); 6.67-6.84 (m, 7H); 7.25-7.42 (m, 10H).

Synthesis of (R,R)-N-(2-Benzyloxy-5-{1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethyl)-phenyl)-formamide (VI)

24 mL (0.63 mol) of formic acid was added to 27 mL (0.28 mol) of acetic anhydride and stirred at 50 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with 100 mL of CH2Cl2 and cooled to 0 °C. A solution of 78 g (0.15 mol) of V in 300 mL de CH2Cl2 was slowly added and stirred for 1h at 0 °C. Then, 150 mL of 10% K2CO3 aqueous solution were added and stirred at 0 °C for 15 min. The organic phase was washed twice with 400 mL of 10% K2CO3 aqueous solution and concentrated under reduced pressure to give 80 g (97% yield, 100% e.e.) (75% chemical purity) of compound VI as an oil. 1H-NMR (200 MHz, CDCl3) δ: 0.98 (d, 3H); 1.42 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.75 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.09 (s, 2H); 6.67-7.41 (m, 17H); 8.4 (d, 1H).

Synthesis (R,R)-N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (VII)

A solution of 8.5 g (16 mmol) of VI, previous purified by column chromatography on silica gel (AcOEt/heptane, 2:3), in 60 mL ethanol was hydrogenated in the presence of 0.14 g of Pd/C 5% at 10 atm. and 40 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and concentrated under reduced pressure to give 5 g (93% yield) (91% chemical purity, 100% e.e.) of compound VII as foam. m. p.= 58-60 °C. 1H-NMR (200 MHz, d6-DMSO) δ: 0.98 (d, 3H); 2.42-2.65 (m, 5H); 3.20-3.40 (m, 1H); 3.71 (s, 3H); 4.43-4.45 (m, 1H); 6.77-7.05 (m, 5H); 8.02 (s, 1H), 8.26 (s, 1H).

Synthesis (R,R)-N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (VII)

A solution of 46 g (0.08 mol) of VI, crude product, was dissolved in 460 mL ethanol and hydrogenated in the presence of 0.74 g of Pd/C 5% at 10 atm. and 40 ° C for 28 h. The mixture was filtered though a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 24 g (83% yield) (77% chemical purity, 100% e.e.) of compound VII as a foam. m. p. = 58-60 °C. 1H-NMR (200 MHz, d6-DMSO) δ: 0.98 (d, 3H); 2.42-2.65 (m, 5H); 3.20-3.40 (m, 1H); 3.71 (s, 3H); 4.43-4.45 (m, 1H); 6.77-7.05 (m, 5H); 8.02 (s, 1H), 8.26 (s, 1H).

The HPLC conditions used for the determination of the Chemical purity % are described in the table below:

  • HPLC Column Kromasil 100 C-18
    Dimensions 0.15 m x 4.6 mm x 5 µm
    Buffer 2.8 ml TEA (triethylamine) pH=3.00 H3PO4 (85%) in 1 L of H2O
    Phase B Acetonitrile
    Flow rate 1.5 ml miN-1
    Temperature 40 °C
    Wavelength 230 nm

    The HPLC conditions used for the determination of the enantiomeric purity % are described in the table below:

    HPLC Column Chiralpak AD-H
    Dimensions 0.25 m x 4.6 mm
    Buffer n-hexane : IPA : DEA (diethyl amine) : H2O 85:15:0.1:0.1
    Flow rate 0.8 ml min-1
    Temperature 25 °C
    Wavelength 228 nm


Example 1

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxy- phenyl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral Intermediate (III) (17. 3g, yield 88%). HPLC: de values of> 90%; MS (ESI) m / z: 541 3 (M ++ 1); 1H-NMR (CDCl3):.. Δ 0. 96 (d, 3H), 1 49 (d, 3H ), 2 · 15 (q, 1Η), 2 · 67 (dq, 2H), 2. 99 (dq, 2H), 3. 74 (s, 3H), 4. 09 (d, 1H), 4. 56 (q, 1H), 5. 24 (s, 2H), 6. 77 (dd, 4H), 7. 10 (d, 1H), 7. 25-7. 5 (m, 11H), 7. 84 ( s, 1H).

 Example 2

 (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) and toluene 100ml, 110 ° C0-flow reactor 36 hours, the solvent was distilled off succeeded intermediates (III) (16. 8g, yield 85%).

Example 3

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene After [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) and dichloromethane 100ml, 30 ° C for 48 hours, and the solvent was distilled off – yl) -N succeeded intermediates (III) (15. Sg, yield 80%).

Example 4

 (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (8. 75g, 32mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral intermediate form (III) (16. 3g, 83% yield).

Example 5

 (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (14. 6g, 54mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral intermediate form (III) (17. 5g, 89% yield).



chirality 1991, 3, 443-50
Fumaric acid (0.138 mmol, 16 mg) was added to the residue dissolved in methanol. Evaporation of the solvent gave the
product (SS) W semifumarate (109 mg) characterized by ‘HNMR (4-D MSO) 6 (ppm) 1.00 (d, 3H, CHCH,), 4.624.70 (m, lH,
CHOH), 3.73 (s, 3H, OCH,), 6.M.9 (m, 3H, aromatic), 7.00 (dd,4H, aromatic), 6.49 (s, 1@ CH = CH fumarate). MS of disilylated
(SS) W: 473 (M +<H3,7%); 367 (M ‘<8H90, 45%); 310 61%). The (RSS) fraction was treated in the same manner
giving the product (R;S) W semifumarate, which was characterized by ‘H-NMR (4-DMSO) 6 (ppm) 1.01 (d, 3H, CHCH,),
3.76 (s, 3H, OC&), 6.49 (s, lH, CH=CH, fumarate) 6.M.9 (m, 3H, aromatic), 7.0 (dd, 4H, aromatic). MS of disilylated (R;S)
(M’X~~HIGNO1,7 %); 178 ( C I ~H~ ~N95O%,) ; 121 (CsH90, W. 473 (M’4H3, 5%); 367 (M’4gH90, 48%); 310
(M +–CI~HIGNO18, %); 178 (CIIHIGNO, 95%); 121 (CsH90, 52%). The structural data for the (RR) and (S;R) enantiomers
were in accordance with the proposed structures. The enantiomeric purity obtained for the enantiomers in each batch is
shown in Table 1.
The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).
Org Process Res Dev1998,2,(2):96

Large-Scale Synthesis of Enantio- and Diastereomerically Pure (R,R)-Formoterol

Process Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752
Org. Proc. Res. Dev., 1998, 2 (2), pp 96–99
DOI: 10.1021/op970116o


(R,R)-Formoterol (1) is a long-acting, very potent β2-agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure (R,R)-formoterol fumarate is achieved by a chromatography-free process with an overall yield of 44%. Asymmetric catalytic reduction of bromoketone 4 using as catalyst oxazaborolidine derived from (1R, 2S)-1-amino-2-indanol and resolution of chiral amine 3 are the origins of chirality in this process. Further enrichment of enantio- and diastereomeric purity is accomplished by crystallizations of the isolated intermediates throughout the process to give (R,R)-formoterol (1) as the pure stereoisomer (ee, de >99.5%).



The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture, which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV). The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI), which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF, yielding the chiral bromoethanol derivative (VIII). The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX), which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X). The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI), which is acylated with formic acid to afford the formamide compound (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, providing the target compound.
The synthesis of the chiral borolidine catalyst (II) starting from indoline (I), as well as the enantioselective reduction of 4′-(benzyloxy)-3′-nitrophenacyl bromide (III), catalyzed by borolidine (II), and using various borane complexes (borane/dimethylsulfide, borane/THF and borane/diethylaniline), has been studied in order to solve the problems presented in large-scale synthesis. The conclusions of the study are that the complex borane/diethylaniline (DEANB) is the most suitable reagent for large-scale reduction of phenacyl bromide (III) since the chemical hazards and inconsistent reagent quality of the borane/THF and borane/dimethylsulfide complexes disqualified their use in large-scale processes. The best reaction conditions of the reduction with this complex are presented.

Formoterol is a long-acting β2-adrenoceptor agonist and has a long duration of action of up to 12 hours. Chemically it is termed as Λ/-[2-hydroxy-5-[1-hydroxy-2-[[2-(4- methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]-formamide. The structure of formoterol is as shown below.

Figure imgf000003_0001

The asterisks indicate that formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four diastereomers which have the following configurations: (R,R), (S1S), (S1R) and (R1S).

(R1R) and (S1S) are mirror images of each other and are therefore enantiomers. Similarly (S1R) and (R1S) form other enatiomeric pair.

The commercially-available formoterol is a 50:50 mixture of the (R1R)- and (S1S)- enantiomers. (R,R)-formoterol is an extremely potent full agonist at the β2-adrenoceptor and is responsible for bronchodilation and has anti-inflammatory properties. On the other hand (S,S)-enantiomer, has no bronchodilatory activity and is proinflammatory.

Murase et al. [Chem.Pharm.Bull., .26(4)1123-1129(1978)] synthesized all four isomers of formoterol and examined for β-stimulant activity. In the process, racemic formoterol was subjected to optical resolution with tartaric acid.

In another attempt by Trofast et al. [Chirality, 3:443-450(1991 )], racemic 4-benzyloxy-3- nitrostryrene oxide was coupled with optically pure N-[(R)-1-phenylethyl]-2-(4- methoxyphenyl)-(R)1-methylethylamine to give diastereomeric mixtures of intermediates, which were separated by column chromatography and converted to the optically pure formoterol.

In yet another attempt, racemic formoterol was subjected to separation by using a chiral compound [International publication WO 1995/018094].

WO 98/21175 discloses a process for preparing optically pure formoterol using optically pure intermediates (R)-N-benzyl-2-(4-methoxyphenyl)-1-methylethyl amine and (R)-4- benzyloxy-3-formamidostyrene oxide.

Preparation of optically pure formoterol is also disclosed in IE 000138 and GB2380996.

Example 7

Preparation of Arformoterol

4-benzyloxy-3-formylamino-α-[N-benzyl-N-(1-methyl-2-p- methoxyphenylethyl)aminomethyl]benzyl alcohol (120gms, 0.23M), 10% Pd/C (12 gms) and denatured spirit (0.6 lit) were introduced in an autoclave. The reaction mass was hydrogenated by applying 4 kg hydrogen pressure at 25-300C for 3 hrs. The catalyst was removed by filtration and the, clear filtrate concentrated under reduced pressure below 400C to yield the title compound. (63 gms, 80%).

Example 8

Preparation of Arformoterol Tartrate

Arformoterol base (60 gms, 0.17M), 480 ml IPA , 120 ml toluene and a solution of l_(+)- tartaric acid (25.6 gms, 0.17M) in 60 ml distilled water were stirred at 25-300C for 2 hrs and further at 40°- 45°C for 3 hrs. The reaction mass was cooled to 25-300C and further chilled to 200C for 30 mins. The solid obtained was isolated by filtration to yield the title compound. (60 gms, 70%),

The tartrate salt was dissolved in hot 50% IPA-water (0.3 lit), cooled as before and filtered to provide arformoterol tartrate. (30 gms, 50 % w/w). having enantiomeric purity greater than 99%.

Organic Process Research & Development 2000, 4, 567-570
 Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a Functionalized Nitroarene: Preparation of a Key Intermediate in the Synthesis of (R,R)-Formoterol Tartrate………..

Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a Functionalized Nitroarene:  Preparation of a Key Intermediate in the Synthesis of (R,R)-Formoterol Tartrate

Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.
Org. Proc. Res. Dev., 2000, 4 (6), pp 567–570
DOI: 10.1021/op000287k
In the synthesis of the β2-adrenoceptor agonist (R,R)-formterol, a key step in the synthesis was the development of a highly chemoselective reduction of (1R)-2-bromo-1-[3-nitro-4-(phenylmethoxy)phenyl]ethan-1-ol to give (1R)-1-[3-amino-4-(phenylmethoxy)phenyl]-2-bromoethan-1-ol. The aniline product was isolated as the corresponding formamide. The reaction required reduction of the nitro moiety in the presence of a phenyl benzyl ether, a secondary benzylic hydroxyl group, and a primary bromide, and with no racemization at the stereogenic carbinol carbon atom. The development of a synthetic methodology using heterogeneous catalytic hydrogenation to perform the required reduction was successful when a sulfur-based poison was added. The chemistry of sulfur-based poisons to temper the reacitivty of catalyst was studied in depth. The data show that the type of hydrogenation catalyst, the oxidation state of the poison, and the substituents on the sulfur atom had a dramatic effect on the chemoselectivity of the reaction. Dimethyl sulfide was the poison of choice, possessing all of the required characteristics for providing a highly chemoselective and high yielding reaction. The practicality and robustness of the process was demonstrated by preparing the final formamide product with high chemoselectivity, chemical yield, and product purity on a multi-kilogram scale.


Tetrahedron: Asymmetry 11 (2000) 2705±2717
An ecient enantioselective synthesis of (R,R)-formoterol, a potent bronchodilator, using lipases
Francisco Campos, M. Pilar Bosch and Angel Guerrero*