13614-98-7

Basic information

• Product Name: Minocycline hydrochloride
• Synonyms: KlinoMycin, Minocycline chloride, MinoMycin, NSC 141993;(4S,4aS,5aR,12aS)-4,7-Bis(diMethylaMino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxaMide hydrochloride;2-Naphthacenecarboxamide, 4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, hydrochloride (1:1), (4S,4aS,5aR,12aS)-;Minocycline hydrochloride Solution, 100ppm;Minocycline hydrochloride, >=98%;[4S-(4alpha,4aalpha,5aalpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-te;10,12,12a-tetrahydroxy-1,11-dioxo--monohydrochloride;minocyclinechloride
• CAS NO: 13614-98-7
• Molecular Formula: C₂₃H₂₇N₃O₇*ClH
• Molecular Weight: 493.94
• EINECS: 237-099-7
• Product Categories: DAYPRO;antibiotic;API;Antibacterial;Antibiotic Explorer;Intermediates & Fine Chemicals;Pharmaceuticals;Peptide Synthesis/Antibiotics
• Mol File: 13614-98-7.mol

Chemical Properties

• Melting Point: 205-210° (dec)
• Boiling Point: 813℃
• Flash Point: >110°(230°F)
• Appearance: yellow/crystalline
• Vapor Pressure: 6.33E-28mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: Sparingly soluble in water, slightly soluble in ethanol (96 per cent). It dissolves in solutions of alkali hydroxides and carbonates.
• Water Solubility: Freely soluble in water
• Stability: Light Sensitive
• Merck: 14,6202
• CAS DataBase Reference: Minocycline hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Minocycline hydrochloride(13614-98-7)
• EPA Substance Registry System: Minocycline hydrochloride(13614-98-7)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• RIDADR: 3249
• WGK Germany: 3
• RTECS: QI7630500
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 13614-98-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Minocycline hydrochloride is used as an antibiotic for its broad-spectrum antibacterial and antiprotozoan activity. It is particularly effective against Gram-positive bacteria, such as staphylococci and streptococci, and has been effective against staphylococcal strains resistant to methicillin and other tetracyclines.
Minocycline hydrochloride is used as an anti-inflammatory agent for its ability to reduce inflammation and prevent neuropathic pain in various conditions, such as in a rat sciatic nerve injury model.
Used in Respiratory Infections:
Minocycline hydrochloride is used as a treatment for chronic bronchitis and other upper respiratory tract infections due to its high serum and tissue levels, despite its relatively low renal clearance.
Used in Urinary Tract Infections:
Minocycline hydrochloride is used for the treatment of urinary tract infections, as it has been effective in the eradication of N. meningitidis in asymptomatic carriers.
Used in Neurological Applications:
Minocycline hydrochloride is used as a neuroprotective agent, attenuating disease severity in mouse models of multiple sclerosis and potentially being effective in methotrexate-induced lung fibrosis.
Used in Research and Development:
Minocycline hydrochloride is used in research for its antiapoptotic properties and its ability to reduce MMP-9 activity, which may have implications for various therapeutic applications.

Therapeutic Function

Antibiotic

Biochem/physiol Actions

Minocycline is a broad spectrum antibiotic with bacteriostatic function. Minocycline has anti-inflammatory properties. Minocycline inhibits lipopolysaccharide mediated inflammatory cytokine tumour necrosis factor (TNF-α) secretion by macrophages. Minocycline inhibits macrophage proliferation in a dose dependent manner. Minocycline inhibits neuroinflammation in pre-plaque of Alzheimer′s disease-like amyloid pathology through inhibition of key inflammatory enzymes like inducible nitric oxide synthase (iNOS), matrix metalloproteinase 9 (MMP-9) and 5-lipoxygenase. Minocycline inhibits endothelial cell proliferation and angiogenesis. Minocycline exhibits anti-tumor activity in glioma by inhibiting membrane type 1 matrix metalloproteinase (MT1-MMP). Minocycline increases cognition and neuronal differentiation. zMinocycline effectively reduces neuropathic pain by increasing the functions of nociceptin/orphanin FQ.

Veterinary Drugs and Treatments

Minocycline may be useful for treating Brucellosis (in combination with aminoglycosides), Lyme disease, and certain nosocomial infections where other more commonly used drugs are ineffective. It has been investigated as adjunctive therapy for treating hemangiosarcomas, but early results have been disappointing.

References

1) Padi and Kulkarni (2008), Minocycline prevents the development of neuropathic pain, but not acute pain: possible anti-inflammatory and antioxidant mechanisms; Eur. J. Pharmacol., 601 79 2) Dziembowska et al. (2013), High MMP-9 activity levels in fragile X syndrome are lowered by minocycline; Am. J. Med. Genet. A, 161A 1897 3) Brundula et al. (2002), Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis; Brain., 125 1297 4) Tikka et al. (2001), Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia; J. Neurosci., 21 2580 5) Kalemci et al. (2013), The efficacy of minocycline against methotrexate-induced pulmonary fibrosis in mice; Eur. Rev. Med. Pharmacol. Sci., 17 3334

InChI:InChI=1/C23H27N3O7.ClH/c1-25(2)12-5-6-13(27)15-10(12)7-9-8-11-17(26(3)4)19(29)16(22(24)32)21(31)23(11,33)20(30)14(9)18(15)28;/h5-6,9,11,17,27,29-30,33H,7-8H2,1-4H3,(H2,24,32);1H/t9-,11-,17-,23-;/m0./s1

Synthetic route

MINOCYCLINE (10118-90-8) → minocycline Hydrochloride (13614-98-7)

Conditions	Yield
With hydrogenchloride In ethanol at 0 - 5℃; for 1h; pH=1 - 2; Solvent;	92.7%

O-benzoyl N,N-dimethylhydroxylamine (58105-38-7) + C24H26N2O9 → minocycline Hydrochloride (13614-98-7)

Conditions	Yield
Stage #1: O-benzoyl N,N-dimethylhydroxylamine; C24H26N2O9 With iron(III) chloride In toluene at 20℃; for 2h; Inert atmosphere; Stage #2: With hydrogenchloride In water for 0.5h;	90%

dimethyl sulfate (77-78-1) + 7-amino-6-desmethyl-6-deoxytetracycline (5679-00-5) → minocycline Hydrochloride (13614-98-7)

Conditions	Yield
With hydrogenchloride; 5%-palladium/activated carbon In 2-methoxy-ethanol; water under 5250.53 - 6750.68 Torr; for 3h;	81.6%

O-benzoyl N,N-dimethylhydroxylamine (58105-38-7) + C28H26N2O8 → minocycline Hydrochloride (13614-98-7)

Conditions	Yield
Stage #1: O-benzoyl N,N-dimethylhydroxylamine; C28H26N2O8 With iron(III) chloride In toluene at 20℃; for 2h; Inert atmosphere; Stage #2: With hydrogenchloride In water for 0.5h;	81%

formaldehyd (50-00-0) + 7-amino-6-desmethyl-6-deoxytetracycline (5679-00-5) → minocycline Hydrochloride (13614-98-7)

Conditions	Yield
With hydrogenchloride; formic acid; 5%-palladium/activated carbon In 2-methoxy-ethanol; water under 5250.53 - 6750.68 Torr; for 3h; Reagent/catalyst;	77.8%

C34H49N3O9Si → minocycline Hydrochloride (13614-98-7)

Conditions	Yield
Stage #1: C34H49N3O9Si With hydrogen fluoride In water; acetonitrile at 23 - 40℃; Stage #2: With hydrogenchloride In water HPLC;	24.6 mg

sancycline (808-26-4, 2696-12-0, 15964-02-0, 39105-46-9) → minocycline Hydrochloride (13614-98-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 1 h / 0 - 5 °C 2.1: iron(III) chloride / toluene / 2 h / 20 °C / Inert atmosphere 2.2: 0.5 h View Scheme

minocycline Hydrochloride (13614-98-7) → <4S-(4α,12aα)>-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-2-naphthacenecarboxamide disulfate

Conditions	Yield
With sulfuric acid; potassium nitrate at 0℃; for 1.5h;	93%
Stage #1: minocycline Hydrochloride With sulfuric acid at 0 - 10℃; under 50 - 300 Torr; for 4.75 - 93.75h; nitrogen flow; Stage #2: With nitric acid In water at 0 - 10℃; for 1.66667 - 2.16667h; Product distribution / selectivity;	93%
With nitric acid; potassium nitrate In cyclohexane; sulfuric acid	90%

minocycline Hydrochloride (13614-98-7) → (4S,4aS,5aR,12S)-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxanaphthacene-2-carboxamide (149934-16-7)

Conditions	Yield
Stage #1: minocycline Hydrochloride With sulfuric acid at 5℃; under 50 - 760.051 Torr; for 3h; Stage #2: With nitric acid In water at 6℃; for 1.66667h; Product distribution / selectivity;	93%
With sulfuric acid; potassium nitrate at 0℃; for 1.5h;	76.6%
With sulfuric acid; potassium nitrate at 0 - 5℃; for 2h; Product distribution / selectivity;
With sulfuric acid; nitric acid In water for 0.5 - 6h; Product distribution / selectivity;
With hydrogenchloride; sulfuric acid; nitric acid In water for 1.66667h; Product distribution / selectivity;

C10H15Cl4NO3 (1075240-45-7) + minocycline Hydrochloride (13614-98-7) → C32H42Cl2N4O9 (1075240-40-2)

Conditions	Yield
With trifluorormethanesulfonic acid In dichloromethane at 24 - 40℃; for 24h; Tscherniac-Einhorn reaction;	76%

1-Iodooctane (629-27-6) + minocycline Hydrochloride (13614-98-7) → 10-O-octyl-7-dimethylamino-6-demethyl-6-deoxytetracycline (1042222-57-0)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 60℃; for 1h;	65%

Iododecane (2050-77-3) + minocycline Hydrochloride (13614-98-7) → 10-O-decyl-7-dimethylamino-6-demethyl-6-deoxytetracycline (1042222-58-1)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 60℃; for 2h;	65%

minocycline Hydrochloride (13614-98-7) + 1-Iodohexane (638-45-9) → 10-O-hexyl-7-dimethylamino-6-demethyl-6-deoxytetracycline (1042222-56-9)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 60℃; for 1h;	64%

1-iodotetradecane (19218-94-1) + minocycline Hydrochloride (13614-98-7) → 10-O-tetradecyl-7-dimethylamino-6-demethyl-6-deoxytetracycline (1042222-60-5)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 60℃; for 3h;	57%

minocycline Hydrochloride (13614-98-7) → MINOCYCLINE (10118-90-8)

Conditions	Yield
With acetic acid In methanol at 42℃; for 3h; Temperature; Reagent/catalyst; Solvent;	55.4%
With sodium hydrogencarbonate In water pH=6.5 - 7.0;

C10H19NO3 (1075240-47-9) + minocycline Hydrochloride (13614-98-7) → C32H44N4O9 (1075240-38-8) + C39H57N5O9 (1075240-39-9)

Conditions	Yield
Stage #1: C10H19NO3; minocycline Hydrochloride With trifluorormethanesulfonic acid at 22℃; for 72h; Tscherniac-Einhorn reaction; Stage #2: C10H19NO3 With trifluorormethanesulfonic acid at 35 - 40℃; for 24h; Tscherniac-Einhorn reaction;	A 53% B 39%

C10H19NO3 (1075240-47-9) + minocycline Hydrochloride (13614-98-7) → C24H29N3O8 (1075240-33-3) + C31H42N4O8 (1075240-37-7)

Conditions	Yield
With trifluorormethanesulfonic acid at 22℃; for 72h; Tscherniac-Einhorn reaction;	A 33% B 50%

1-Iodododecane (4292-19-7) + minocycline Hydrochloride (13614-98-7) → 10-O-dodecyl-7-dimethylamino-6-demethyl-6-deoxytetracycline (1042222-59-2)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 60℃; for 3h;	46%

minocycline Hydrochloride (13614-98-7) → (4S,4aS,5aR,12aS)-4-Dimethylamino-3,7,10,12,12a-pentahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide; hydrochloride (135513-29-0)

Conditions	Yield
With ascorbic acid; potassium hexacyanoferrate(III) 1) 2) H2O;

minocycline Hydrochloride (13614-98-7) → [6S-(2bα,6α,6aα,7aα)]-6,9-bis(dimethylamino)-1,2b,3,6,6a,7,7a,8-octahydro-2b,5,12-trihydroxy-3-oxo-1,2-diazacyclopenta[fg]naphthacene-4-carboxylic acid amide + [5S-(5α,5aα,6aα,12baα,12cα)]-5,8-bis(dimethylamino)-1,5,5a,6,6a,7,12,12a,12b,12c-decahydro-4,11,12b,12c-tetrahydroxy-12-oxo-1,2-diazacyclopenta[de]naphthacene-3-carboxylic acid amide

Conditions	Yield
With hydrazine hydrate In water at 20℃; for 16h;

minocycline Hydrochloride (13614-98-7) → [((5aR,6aS,7S,10aS)-9-Carbamoyl-4,7-bis-dimethylamino-1,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydro-naphthacen-2-ylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (153621-82-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / KNO3, H2SO4 / 1.5 h / 0 °C 2: 96 percent / H2, 2 N aq. H2SO4 / 10percent Pd/C / 2-methoxy-ethanol / 1.5 h / 2068.6 Torr 3: 65 mg / AcONa / tetrahydrofuran; H2O / 2 h View Scheme

minocycline Hydrochloride (13614-98-7) → <4S-(4α,12aα)>-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide disulfate

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / KNO3, H2SO4 / 1.5 h / 0 °C 2: 96 percent / H2, 2 N aq. H2SO4 / 10percent Pd/C / 2-methoxy-ethanol / 1.5 h / 2068.6 Torr View Scheme
Stage #1: minocycline Hydrochloride With sulfuric acid; potassium nitrate at -5 - -1℃; Stage #2: With hydrogen; palladium 10% on activated carbon at 20 - 25℃; under 2585.81 Torr;

minocycline Hydrochloride (13614-98-7) → <4S-(4α,12aα)>-9-<(aminoacetyl)amino-4,7-bis(dimethylamino)>-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide monotrifluoroacetate

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / KNO3, H2SO4 / 1.5 h / 0 °C 2: 96 percent / H2, 2 N aq. H2SO4 / 10percent Pd/C / 2-methoxy-ethanol / 1.5 h / 2068.6 Torr 3: 65 mg / AcONa / tetrahydrofuran; H2O / 2 h 4: 65 mg / 5 h / Ambient temperature View Scheme

minocycline Hydrochloride (13614-98-7) → <4S-(4α,12aα)>-9-(acetylamino)-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / KNO3, H2SO4 / 1.5 h / 0 °C 2: 96 percent / H2, 2 N aq. H2SO4 / 10percent Pd/C / 2-methoxy-ethanol / 1.5 h / 2068.6 Torr 3: Na2CO3, N,N-dimethylpropyleneurea / acetonitrile / 0.5 h / Ambient temperature View Scheme

minocycline Hydrochloride (13614-98-7) → <4S-(4α,12aα)>-4,7-bis(dimethylamino)-9-<<(dimethylamino)acetyl>amino>-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / KNO3, H2SO4 / 1.5 h / 0 °C 2: 96 percent / H2, 2 N aq. H2SO4 / 10percent Pd/C / 2-methoxy-ethanol / 1.5 h / 2068.6 Torr 3: Na2CO3, N,N-dimethylpropyleneurea / acetonitrile / 0.5 h / Ambient temperature View Scheme

minocycline Hydrochloride (13614-98-7) → [6S-(2bα,6a,6aα,7aα)]-6,9-bis(dimethylamino)-1,2b,3,6,6a,7,7a,8-octahydro-2b,5,12-trihydroxy-3-oxo-1,2-diaza-cyclopenta[fg]naphthacene-4-carboxylic acid amide + (5S)-(5a,5aα,6aα,12bα,12cα)-5,8-bis(dimethylamino)-1,5,5a,6,6a,7,12,12a,12b,12c-decahydro-4,11,12b,12c-tetrahydroxy-12-oxo-1,2-diaza-cyclopenta[de]naphthacene-3-carboxylic acid amide

Conditions	Yield
Stage #1: minocycline Hydrochloride With hydrazine In water at 20℃; Stage #2: With trifluoroacetic acid In water; acetonitrile Stage #3: With triethylamine In water

minocycline Hydrochloride (13614-98-7) → [4S-(4a,12aα)]-12-amino-4,7-bis(dimethylamino)-3,10,12a-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide

Conditions	Yield
With ammonia In ethanol at 20℃; for 4h; Heating / reflux;

C10H13F6NO3 (1075240-32-2) + minocycline Hydrochloride (13614-98-7) → C24H29N3O8 (1075240-33-3) + C32H41F3N4O9 (1075240-34-4)

Conditions	Yield
With trifluorormethanesulfonic acid at 22℃; Tscherniac-Einhorn reaction;	A 50 %Chromat. B 30 %Chromat.

C10H13F6NO3 (1075240-32-2) + minocycline Hydrochloride (13614-98-7) → C25H31N3O9

Conditions	Yield
Stage #1: C10H13F6NO3; minocycline Hydrochloride With trifluorormethanesulfonic acid at 22℃; Tscherniac-Einhorn reaction; Stage #2: In trifluorormethanesulfonic acid at 22℃; for 18h;

C10H13Cl6NO3 (1075240-44-6) + minocycline Hydrochloride (13614-98-7) → C26H31N3O9 (1075240-36-6) + C26H33N3O10 (1075240-35-5)

Conditions	Yield
With trifluorormethanesulfonic acid Tscherniac-Einhorn reaction;

C10H15Cl4NO3 (1075240-45-7) + minocycline Hydrochloride (13614-98-7) → C24H29N3O8 (1075240-33-3) + C31H40Cl2N4O8

Conditions	Yield
With trifluorormethanesulfonic acid at 22℃; for 0.5h; Tscherniac-Einhorn reaction;

Upstream product

• 58105-38-7 O-benzoyl N,N-dimethylhydroxylamine 
• 808-26-4 sancycline 
• 10118-90-8 MINOCYCLINE 
• 50-00-0 formaldehyd 
• 5679-00-5 7-amino-6-desmethyl-6-deoxytetracycline 
• 77-78-1 dimethyl sulfate 
• 64-73-3 demeclocycline hydrochloride 

Downstream Products

• 151922-16-6 9-(N,N-dimethylglycylamido)-minocycline 
• 864073-42-7 [4S-(4a,12aα)]-12-amino-4,7-bis(dimethylamino)-3,10,12a-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide 
• 149934-16-7 (4S,4aS,5aR,12S)-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxanaphthacene-2-carboxamide 
• 1075240-33-3 C₂₄H₂₉N₃O₈ 
• 1075240-34-4 C₃₂H₄₁F₃N₄O₉ 
• 1075240-37-7 C₃₁H₄₂N₄O₈ 
• 10118-90-8 MINOCYCLINE 
• 389139-89-3 Omadacycline 

Relevant articles and documents

Preparation method of 7-amino-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride

The invention relates to a preparation method of 7-amido-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride, and particularly provides a preparation method of 7-amido-6-demethylation-6-deoxy tetracycline. The preparation method comprises the following steps: (1) carrying out chlorination reaction on 6- preparation method-6-deoxy tetracycline and a chlorination reagent, and obtaining a chlorination product; carrying out azo reaction on the chlorination product and an azo reagent to obtain a reaction solution containing 7-p-benzenesulfonic acid azo group-11a-chloro-6-demethylation-6-deoxy tetracycline; and (2) adding a reducing reagent into the reaction solution containing the 7-p-benzenesulfonic acid azo group-11a-chloro-6-demethylation-6-deoxy tetracycline obtained in the step (1), and carrying out a reaction to obtain the 7-amido-6-demethylation-6-deoxy tetracycline. The synthesis method of minocycline hydrochloride has the advantages of simple synthesis process, high yield, high purity, easiness in large-scale production and the like.

Synthesis method of minocycline hydrochloride

The invention relates to a synthesis method of minocycline hydrochloride, which comprises the following steps of: (1) reacting demeclocycline with an amination reagent in a first organic solvent in the presence of a palladium metal complex to obtain 7-amino-6-demethyltetracycline; (2) carrying out a dehydroxylation reaction on the 7-amino-6-demethyltetracycline in a second organic solvent in the presence of a first acid reagent and a first catalyst, so as to obtain 7-amino-6-demethyl-6-deoxytetracycline; and (3) in a third organic solvent, in the presence of a second acid reagent and a second catalyst, carrying out alkylation reaction on the 7-amino-6-demethyl-6-deoxytetracycline and an alkylation reagent to obtain minocycline hydrochloride. The minocycline hydrochloride prepared by the method disclosed by the invention has the advantages of simple synthesis process, high yield, high purity and easiness in large-scale production.

Synthesis method of minocycline hydrochloride

The invention discloses a preparation method of minocycline hydrochloride. The preparation method is characterized by comprising the following steps: with demeclocycline hydrochloride as an initial raw material, carrying out a dehydroxylation reaction to obtain 6-deoxy-6-demeclocycline (intermediate I for short); carrying out acetyl protection on the intermediate I to obtain 3,10,12,12a-tetraacetyl-6-deoxy-6-demeclocycline (intermediate II for short); carrying out the BuchwaldHartwig reaction on the intermediate II to obtain 3,10,12,12a-tetraacetylminocycline (intermediate III for short); hydrolyzing the intermediate III to obtain minocycline free alkali (intermediate IV for short); and salifying the intermediate IV to obtain minocycline hydrochloride. According to the invention, nitrification, diazotization and azo reactions used in traditional minocycline hydrochloride synthesis processes are avoided, so dangerous factors in the production process are reduced, operation is simple, environmental pollution is avoided, and the method has industrial production prospects.

Preparation method of minocycline

The invention discloses a preparation method of minocycline. The minocycline is (4S,4aS,5aR,12aS)-4,7-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-tetraphenyl-2-formamide. According to the method, sancyline is subjected to protection of a phenolic hydroxyl group via an acyl group, and then selective dimethylamination is conducted on position 6. After a protection strategy is adopted in the process route of the method, generation of 9-position dimethylamination by-products is avoided, and purification is simple. Usage of precious metal is avoided in a reaction, a production unit is simple to operate, safe and environment-friendly, and the method is very suitable for industrial production.

A robust platform for the synthesis of new tetracycline antibiotics

Tetracyclines and tetracycline analogues are prepared by a convergent, single-step Michael-Claisen condensation of AB precursor 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at -78 °C, while Claisen cyclization of the enolate produced is rate-determining, typically occurring upon warming to 0 °C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semisynthetic methods (presently the only means of tetracycline production) and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.

Isolation and recovery of calcium chloride complex of 7-dimethylamino-6-dimethyl l-6-deoxytetracycline hydrochloride

This disclosure describes a process for the recovery of 7-dimethylamino-6-demethyl-6-deoxytetracycline from an aqueous solution thereof by means of a calcium chloride complex of 7-dimethylamino-6-demethyl-6-deoxy-tetracycline hydrochloride.