3963-95-9

Basic information

• Product Name: Metacycline hydrochloride
• Synonyms: Methacycline HCl (PhysioMycine);6-Methyleneoxytetracycline hydrochloride, Metacycline hydrochloride, LondoMycin;(4S,4aR,5S,5aR,12aS)- 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methylene-1,11-dioxo-2-naphthacenecarboxamide, hydrochloride (1:1);Methacycline hydrochloride Solution, 100ppm;Hydrochloric acid methacycline;Rondomycin hydrochloride;6-DEMETHYL-6-DEOXY-6-METHYLENEOXYTETRACYCLINE MONOHYDROCHLORIDE;6-DEMETHYL-6-DEOXY-6-METHYLENEOXYTETRACYCLNE HYDROCHLORIDE
• CAS NO: 3963-95-9
• Molecular Formula: C₂₂H₂₂N₂O₈*ClH
• Molecular Weight: 478.88
• EINECS: 223-568-3
• Product Categories: NUBAIN;API;Amines;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 3963-95-9.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 813.8 °C at 760 mmHg
• Flash Point: 445.9 °C
• Appearance: Yellow/Crystalline Powder
• Vapor Pressure: 5.4E-28mmHg at 25°C
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: DMSO (Slightly, Heated), Methanol (Slightly, Heated, Sonicated), Water (Slightly
• BRN: 5470951
• CAS DataBase Reference: Metacycline hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Metacycline hydrochloride(3963-95-9)
• EPA Substance Registry System: Metacycline hydrochloride(3963-95-9)

Safety Data

• Safety Statements: 24/25-22
• WGK Germany: 2
• RTECS: QI9276000
• Hazardous Substances Data: 3963-95-9(Hazardous Substances Data)

Usage

Description

Metacycline hydrochloride, also known as methacycline hydrochloride or Rondomycin, is a broad-spectrum, semisynthetic antibiotic belonging to the tetracycline class. It is derived from oxytetracycline through chemical modification and exhibits greater potency compared to other tetracyclines. Metacycline hydrochloride is a yellow to dark yellow, crystalline powder that is slightly soluble in water and insoluble in nonpolar solvents. It is characterized by its longer serum half-life and greater stability in both in vivo and in vitro conditions.

Uses

1. Used in Pharmaceutical Industry:
Metacycline hydrochloride is used as an antibiotic for its broad-spectrum antibacterial and antiprotozoan activity. It is effective against a wide range of Gram-positive and Gram-negative organisms, making it a valuable treatment option for various bacterial infections.
2. Used as an Analgesic:
Metacycline hydrochloride is used as an analgesic, helping to relieve pain caused by bacterial infections or other conditions.
3. Used as a Narcotic Antagonist:
Metacycline hydrochloride is also used as a narcotic antagonist, which can be beneficial in the treatment of drug addiction or overdose.
4. Used in Veterinary Medicine:
Metacycline hydrochloride is used as a veterinary antibiotic for treating bacterial infections in animals, thanks to its broad-spectrum activity and potent effects.
5. Used in Research and Development:
Due to its unique chemical properties and stability, Metacycline hydrochloride is utilized in research and development for the creation of new antibiotics and pharmaceutical compounds.

Originator

Rondomycin ,Pfizer ,UK ,1963

Manufacturing Process

To a stirred solution of 4.6 g (0.01 mol) of anhydrous oxytetracycline in 40 ml of dry tetrahydrofuran is added 3.5 g (0.021 mol) of pyridine-sulfur trioxide complex. After 16 hours of stirring at room temperature, the resulting suspension is filtered, and the solid is slurried with 25 ml of 2% hydrochloric acid for 10 minutes, filtered and thoroughly washed with methanol followed by ether. The pale yellow crystalline 5-oxytetracycline-6,12-hemiketal-12-sulfuric acid ester melts at 210°C.500 mg 5-oxytetracycline-6,12-hemiketal-12-sulfuric acid ester, prepared as described, is added to 4 ml dry liquid hydrogen fluoride, and the mixture is stirred for 1.5 hours at ice bath temperature. The hydrogen fluoride is then evaporated in a stream of nitrogen and the resulting gummy solids are triturated with about 15 ml ether and filtered. The resulting solid hydrofluoride salt is further purified by suspending in water, adjusting the pH to about 4, and extracting the 6-methylene-5-oxytetracycline free base from the aqueous phase with ethyl acetate. The extract is separated and evaporated to dryness under reduced pressure. The resulting residue is triturated with ether and filtered, and the solid is recrystallized from methanol-acetone-etherconcentrated hydrochloric acid to obtain the product as a purified hydrochloride, according to US Patent 3,026,354.

Therapeutic Function

Antibiotic

InChI:InChI=1/C22H22N2O8.ClH/c1-7-8-5-4-6-9(25)11(8)16(26)12-10(7)17(27)14-15(24(2)3)18(28)13(21(23)31)20(30)22(14,32)19(12)29;/h4-6,10,14-15,17,25,27-29,32H,1H2,2-3H3,(H2,23,31);1H

Synthetic route

methacycline hydrochloride (3963-95-9) → doxycycline (564-25-0) + 6-epidoxycycline (3219-99-6)

Conditions	Yield
With hydrogen; closo-3,3-(η2,η3-C7H7CH2)-3,1,2-RhC2B9H11 In methanol at 43℃; under 76000 Torr; for 4h;	A 95.5% B 2%
With hydrogen; rhodium-carborane complex B In methanol at 100℃; under 76000 Torr; for 4h;	A 41% B 52.5%
With hydrogen; In methanol at 60℃; under 76000 Torr; for 4h;	A 96 % Chromat. B 2.5 % Chromat.
With hydrogen; In methanol at 60℃; under 76000 Torr; for 4h; Yield given. Yields of byproduct given;
With hydrogen; closo-(ϖ-cyclodienyl)rhodacarborane In methanol at 60℃; under 76000 Torr; for 4h; Product distribution; various catalyst;	A 96 % Chromat. B 2.5 % Chromat.

methacycline hydrochloride (3963-95-9) + C10H16BO3 → [4S-(4α,12aα)]-4-(dimethylamino)-6-(4-tert-butylbenzylidene)-3,5,10,12,12a-pentahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxamide

Conditions	Yield
With copper dichloride In methanol Heating;	43%

methacycline hydrochloride (3963-95-9) + (4-chlorophenyl)methanethiol (6258-66-8) → 13-<(4-chlorobenzyl)thio>-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 2h; Heating;	35.2%

methacycline hydrochloride (3963-95-9) + 2-propanethiol (75-33-2) → 13-(isopropylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	32.4%

cyclopentylthiol (1679-07-8) + methacycline hydrochloride (3963-95-9) → 13-(cyclopentylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	32.1%

Hexanethiol (111-31-9) + methacycline hydrochloride (3963-95-9) → 13-(hexylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	31.5%

2-methylpropanethiol-1 (513-44-0) + methacycline hydrochloride (3963-95-9) → 13-(isobutylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	29.5%

3,4-dichlorobenzyl mercaptan (36480-40-7) + methacycline hydrochloride (3963-95-9) → 13-<(3,4-dichlorobenzyl)thio>-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 2h; Heating;	29.2%

thiophenol (108-98-5) + methacycline hydrochloride (3963-95-9) → 13-(phenylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 6h; Heating;	27.1%

methacycline hydrochloride (3963-95-9) + phenylmethanethiol (100-53-8) → 13-(benzylthio)-5-hydroxy-6-α-deoxytetracycline (146253-75-0)

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 2h; Heating;	26%

methacycline hydrochloride (3963-95-9) + p-Chlorothiophenol (106-54-7) → 13-<(4-chlorophenyl)thio>-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 6h; Heating;	25.3%

1-thiopropane (107-03-9) + methacycline hydrochloride (3963-95-9) → 13-(propylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	25%

1-butanethiol (109-79-5) + methacycline hydrochloride (3963-95-9) → 13-(butylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	23%

methacycline hydrochloride (3963-95-9) + ethanethiol (75-08-1) → 13-(ethylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	22.9%

3-chloropropanethiol (17481-19-5) + methacycline hydrochloride (3963-95-9) → 13-(3-chloropropylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	21.4%

para-bromobenzenethiol (106-53-6) + methacycline hydrochloride (3963-95-9) → 13-<(4-bromophenyl)thio>-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 6h; Heating;	21%

rac-3-sulfanylpropane-1,2-diol (96-27-5) + methacycline hydrochloride (3963-95-9) → 13-<(2,3-dihydroxypropyl)thio>-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	19.3%

methacycline hydrochloride (3963-95-9) + 2-hydroxyethanethiol (60-24-2) → 13-<(2'-hydroxyethyl)thio>-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
at 100℃; for 0.5h;	19.3%

4-Methoxybenzenethiol (696-63-9) + methacycline hydrochloride (3963-95-9) → 13-<(4-methoxyphenyl)thio>-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 6h; Heating;	18.9%

methylthiol (74-93-1) + methacycline hydrochloride (3963-95-9) → 13-(methylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol at 70℃; for 4h;	18.4%

methacycline hydrochloride (3963-95-9) + 3-mercaptopropionic acid (107-96-0) → 13-<(2-carboxyethyl)thio>-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	17.3%

2-methylpropan-2-thiol (75-66-1) + methacycline hydrochloride (3963-95-9) → 13-(tert-butylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 10h; Heating;	15.2%

Cyclohexanethiol (1569-69-3) + methacycline hydrochloride (3963-95-9) → 13-(cyclohexylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	15%

decylthiol (143-10-2) + methacycline hydrochloride (3963-95-9) → 13-(n-decylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	14.3%

methacycline hydrochloride (3963-95-9) + 3-methylbutanethiol (541-31-1) → 13-(isopentylthio)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In ethanol for 12h; Heating;	11.3%

methacycline hydrochloride (3963-95-9) → 13-(benzylsulfonyl)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
Multi-step reaction with 2 steps 1: 26 percent / AIBN / ethanol / 2 h / Heating 2: 50 mg / 0.1M aq. oxone / ethanol / 1 h / Ambient temperature View Scheme

methacycline hydrochloride (3963-95-9) → 13-(cyclopentylthio)-5-hydroxy-6-α-deoxy-N-(morpholionemethyl)tetracycline

Conditions	Yield
Multi-step reaction with 2 steps 1: 32.1 percent / AIBN / ethanol / 12 h / Heating 2: 77.8 percent / 2-methyl-propan-2-ol; H2O / 1.) RT, 30 min, 2.) reflux, 15 min View Scheme

methacycline hydrochloride (3963-95-9) → 13-(benzylsulfinyl)-5-hydroxy-6-α-deoxytetracycline

Conditions	Yield
Multi-step reaction with 2 steps 1: 26 percent / AIBN / ethanol / 2 h / Heating 2: 35 percent / 0.1M aq. oxone / ethanol / 0.42 h / Ambient temperature View Scheme

methacycline p-toluene sulfonate + methacycline hydrochloride (3963-95-9) → doxycycline

chlorotris(triphenylphosphane)rhodium(I) + methacycline (914-00-1, 138245-75-7) + toluene-4-sulfonic acid (104-15-4) + methacycline hydrochloride (3963-95-9) → doxycycline p-toluenesulphonate

Conditions	Yield
With hydrazine In methanol

Downstream Products

• 146253-75-0 13-(benzylthio)-5-hydroxy-6-α-deoxytetracycline 
• 564-25-0 doxycycline 
• 3219-99-6 6-epidoxycycline 
• 146253-86-3 13-(3-chloropropylthio)-5-hydroxy-6-α-deoxytetracycline 

Relevant articles and documents

Manufacture of 6-methylenetetracyclines

Methacycline (6-methylene-5-oxytetracycline) is prepared by halogenating oxytetracycline (5-hydroxytetracycline) to produce the 11a-halo-6,12-hemiketal, under conditions which form and maintain the product in the enolic form, reacting the hemiketal base with acid to produce the hemiketal acid salt, dehydrating the acid salt to form 11a-halo-6-methylene-5-oxytetracycline, and reducing the compound to the salt of 6-methylene-5-oxytetracycline. An improved method for producing the 6-methylenetetracycline base from the product salt is also disclosed. The process is applicable to the synthesis of 6-methylenetetracycline per se or other 6-methylenetetracyclines, as well as methacycline.