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[ CAS No. 13614-98-7 ] {[proInfo.proName]}

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Chemical Structure| 13614-98-7
Chemical Structure| 13614-98-7
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Product Details of [ 13614-98-7 ]

CAS No. :13614-98-7 MDL No. :MFCD00083669
Formula : C23H28ClN3O7 Boiling Point : -
Linear Structure Formula :- InChI Key :WTJXVDPDEQKTCV-VQAITOIOSA-N
M.W : 493.94 Pubchem ID :54685925
Synonyms :
Minocycline HCl;CL 59806

Calculated chemistry of [ 13614-98-7 ]

Physicochemical Properties

Num. heavy atoms : 34
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.43
Num. rotatable bonds : 3
Num. H-bond acceptors : 8.0
Num. H-bond donors : 5.0
Molar Refractivity : 125.54
TPSA : 164.63 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.71 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.85
Log Po/w (WLOGP) : 0.99
Log Po/w (MLOGP) : -1.39
Log Po/w (SILICOS-IT) : -0.5
Consensus Log Po/w : -0.01

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.11

Water Solubility

Log S (ESOL) : -3.37
Solubility : 0.21 mg/ml ; 0.000426 mol/l
Class : Soluble
Log S (Ali) : -3.89
Solubility : 0.0636 mg/ml ; 0.000129 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.12
Solubility : 3.76 mg/ml ; 0.0076 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 5.15

Safety of [ 13614-98-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335-H351-H361 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 13614-98-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 13614-98-7 ]

[ 13614-98-7 ] Synthesis Path-Downstream   1~64

  • 1
  • [ 13614-98-7 ]
  • [ 135513-29-0 ]
  • 2
  • [ 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 [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% To evaluate whether the above findings can be reproducible on larger scale, a nitration reaction was conducted on 500 g of <strong>[13614-98-7]minocycline</strong> in a 5-L jacketed cylindrical reactor. To ensure that complete success can be achieved at commercial scale, the reaction conditions and reactor vessel parameters defined in the commercial batches were closely emulated in scaled-down reactors. Described in Table 13 is a comparison of the reactor vessel specifications used in the nitration reaction on commercial batches vs. the parameters used in our scaled-down equipment.The scaled down agitation speed was calculated based on the following geometric similarity mixing equation:where rpm2=scaled down equipment agitator speed (rpm) rpm1=large-scale equipment agitator speed (rpm) V1=maximum volume (L) on large scale equipment V2=maximum volume (L) on scaled down equipment D1=diameter (mm) of agitator on large scale equipment D2=diameter (mm) of agitator on scaled-down equipment The commercial supply batches were typically performed on 186 kg of <strong>[13614-98-7]minocycline</strong> starting material. The estimated maximum volume in the reactor was 700 L and for the scaled-down experiments, the maximum volume measured was 2 L on 500 g scale. The geometric similarity calculation is based on the assumption that reactor shape and size ratios are held equal.In a 5-L ChemGlass jacketed cylindrical reactor, <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> was added to and dissolved in concentrated sulfuric acid at 0-10 C. The nitrogen flow was set at 0.2 SCFH and agitation rate at 492-500 rpm. The addition took 1 hr 45 min. A vacuum was applied at 287-300 torr for 3 hr. The mixture was allowed to stand at 0-5 C. (50 rpm) for 71 hr followed by vacuum at 50 torr for 1 hr and stand for another 17 hr. Data in Table 14 summarizes the purity and chloride content at different sampling points. The starting material <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> contained 6.8% HCl. TABLE 13 REACTOR SPECIFICATIONS FOR 5-L NITRATION REACTION RA3-109 CG-1929-28* Reactor volume capacity 4220 5 (L) Reactor diameter (mm) 1600 176 Agitator diameter (mm) 1290 135 Agitator type Anchor + turbine Teflon paddle anti foam (half-moon) Baffles 2 (180)-radial, 1 external (1 cm externaldiameter)§ Temperature probe 700 mm from center 0.25 diameter, position 48 mm from center Temperature probe Min volume 300 litres Bottom of probe situated at the 1-liter mark of reactor Agitation speed (rpm) 74500¥ Nitric acid charge setup Dip tube above surface Dip tube 13 cm above surface HCl purge Headspace, PTFE Vacuum (50-300 torr) lining 3 *ChemGlass, Vineland, NJ.§Bottom of the baffle situated at 1-liter mark of the reactor.¥Calculated agitation speed was 452 rpm. TABLE 14 PURITY AND CHLORIDE CONTENT OF MINOCYCLINE IN SULFURIC ACID Minocycline purity Chloride Experiment Sampling point (Total impurity, %) content (ppm) 1 Minocycline - 68000 2 Before vacuum 9.68 364 3 After vacuum at 9.95 <50* 300 torr for 3 hr 4 After 65 hr hold at 8.33 <50 0-5 C. 5 After vacuum at 8.73 <50 50 torr for 1 hr and 17 hr hold *reporting limit: 50 ppmEffective removal of HCl was achieved after 3 hr mixing (500 rpm) at 300 torr. After removing HCl from the system after sampling for HCl content (Experiment 4), the <strong>[13614-98-7]minocycline</strong> was nitrated. The agitation rate was set at 500 rpm and nitric acid was added over 100 mins via a dip tube situated 13 cm above the surface of the reaction mixture. The reaction was completed (starting material was undetected by HPLC) using 1.2 eq nitric acid. Minocycline was less than 1.0%. The cold reaction mixture was transferred over 1 hr to a mixture of IPA:heptane (13.7 L IPA, 1.65 L heptane) kept at 0-12 C. in a 20-L ChemGlass jacketed reactor. The precipitated product was mixed at 0-10 C. overnight, filtered, washed with IPA:heptane (3.225 L IPA, 0.55 L heptane) followed by IPA (3.6 L). The product was dried at 40-42 C. to provide 613 g (93% yield) of 9-nitro<strong>[13614-98-7]minocycline</strong> sulfate. This procedure described above was repeated in the demonstration batch (see further ahead).The purity of the 9-nitro<strong>[13614-98-7]minocycline</strong> produced was 76.5%. This purity was comparable or superior to the purity obtained in typical commercial batches.This would be expected given the supplemental vacuum removal of residual HCl before nitration in this experiment. This operation step led to a much cleaner 9-nitro<strong>[13614-98-7]minocycline</strong> material. Comparison of the purity profile data collected for this experiment (pre-demo 500 g) with typical batches is presented in Table 15. TABLE 15 9-NITROMINOCYCLINE PURITY PROFILE Area % HPLC Relative Retention Time Mino IMP B IMP B Epi 9-Nitro IMP A Description 0.25 0.29 0.37 0.44 0.59 0.68 0.78 0.88 0.93 0.97 1.00 1.09 1.15 NO2 sulfate(oven dry) 0.68 <0.1 0.77 1.40 5.54 4.25 1.29 1.53 2.55 1.72 76.27 <0.1 1.34 NO2 sulfate (N2 dry) 0.64 <0.1 0.92 0.09 2.94 3.17 1.57 6.13 5.48 2.45 72.91 0.26 0.25 NO2 HCl (oven dry) 1.24 <0.1 1.51 1.85 8.78 7.06 3.58 2.58 4.22 1.46 61.65 0.30 1.92 NO2 HCl (N2 dry) 1.22 <0.1 1.44 1.74 10.23 7.05 3.91 2.08 2.91 1.33 61....
90% With nitric acid; potassium nitrate; In cyclohexane; sulfuric acid; 1) Preparation of 9-Nitro Minocycline Minocycline hydrochloride (1, 100 g, 0.202 mol) is dissolved in 300 ml of a concentrated sulfuric acid which is pre-cooled to 0 C., and then under the temperature of -5 C. to 5 C., potassium nitrate (22.4 g, 0.24 mol) or fuming nitric acid (11.3 ml, 0.24 mol) are slowly added thereto. After the addition is completed, the mixture is continuously stirred for 1.5 hours at the temperature of from -5 to 5 C.; 2.4 L of a pre-cooled cyclohexane is slowly added, filtered, and washed with a small amount of ice cyclohexane, and the obtained solids are collected. The solids are dried under vacuum at 40 to 50 C. to give a yellow 9-nitro <strong>[13614-98-7]minocycline</strong> disulfate (2, 124.8 g, about 90%).
52 - 100% Comparative Example 2: Preparation of 9-nitrominocvcline[0150] This Example describes the nitration of <strong>[13614-98-7]minocycline</strong> where the product of the nitration is isolated.[0151] A 2-L multi-neck glass flask was equipped with a mechanical stirrer, thermocouple, liquid addition tube, nitrogen line, and gas outlet to a 30% (wt.) EPO <DP n="46"/>caustic scrubber. The flask was charged with sulfuric acid 66 Be (1 ,507 g, 819 mL, 15 moles). The solution was cooled to 0 - 20C. Minocycline. HCI (92.7% potency, 311 g, 0.58 moles) was added to the sulfuric acid over 0.7 hours at 0 - 14 0C with stirring. After addition, the mixture was stirred at O0C for 0.5 hours to obtain a yellow solution. Nitric acid (95.9% nitrate content, 48 g, 32 mL, 0.73 moles, 1.25 mol equivalents) was added over 3 hours while keeping the mixture at 0 - 2 0C. The mixture was stirred at O0C for 0.3 hours (dark red/black solution). Analysis (area %) by HPLC showed: 0% <strong>[13614-98-7]minocycline</strong>, 75.6% 9-nitro<strong>[13614-98-7]minocycline</strong>, 8.2% largest single impurity (LSI); relative retention time to <strong>[13614-98-7]minocycline</strong> (RRT) = 2.08.[0152] A 22-L multi-neck glass flask was equipped with a mechanical stirrer, thermocouple, and a condenser with nitrogen protection. The flask was charged with 6,704 g (8,540 mL) of isopropanol (IPA) and 1 ,026 g (1 ,500 mL) of heptanes. The solution was then cooled to 0 - 5C. The 9-nitro<strong>[13614-98-7]minocycline</strong> reaction mixture was transferred to the 22-L flask over 2 hours at 0 - 39 C to yield a yellow slurry. The slurry temperature was maintained at 34 - 39C for 2 hours then cooled to 20 - 34C and stirred at 20 - 34 0C for 14.6 hours.[0153] A solution of isopropanol 3,028 g (3,857 mL) and heptanes 660 g (965 mL) was prepared and maintained at 20 - 25C (4:1 , 1 PA: heptanes by volume). The slurry was filtered on a 30-cm diameter Bchner funnel using No.1 Whatman filter paper under vacuum and nitrogen protection. The resulting wet cake was transferred to a 4-L glass Erlenmeyer flask, equipped with a mechanical stirrer and nitrogen protection. The cake was slurried by adding 1 ,608 mL of the prepared IPA/heptanes solution for 0.5 hours at 23 - 26C.[0154] The slurry was filtered again as described above. The wet cake was reslurried two more times as above (total of three reslurries). After the last filtration, the cake was maintained under vacuum under nitrogen protection for 0.2 hours. The product was dried at 400C under 23 - 11 mmHg of vacuum for 48 hours to a loss on drying (LOD, 800C, 1 hour, > 49 mmHg vacuum) value of 1.54. The weight of 9-nitro<strong>[13614-98-7]minocycline</strong> sulfate obtained was 380.1Og, HPLC strength = 76.3% (as the disulfate salt), total impurities = 34.6%, largest single impurity (LSI) 9.46% (RRT = 0.94). Yield from <strong>[13614-98-7]minocycline</strong>.HCI = 86%. Yield corrected for strength of product and starting material = 71%. EPO <DP n="47"/>[0155] It can be seen that isolating the 9-nitro<strong>[13614-98-7]minocycline</strong> compound resulted in a product having a large percentage of impurities.Example 1[0156] Table 2 below outlines nitration experiments conducted using the procedure outlined in Comparative Example 2, where the following variables were modified: nitric acid addition time; reaction temperature; molar equivalents of nitric acid (relative to <strong>[13614-98-7]minocycline</strong> HCI); and agitation rate. In accordance with the methods disclosed herein, none of these reactions were quenched or worked up to isolate product. The sole analytical tool used was HPLC analysis. EPO <DP n="48"/>Table 21 Only the bath temperature was monitored in these reactions due to vessel size.2 Reaction was at 50wt% of original <strong>[13614-98-7]minocycline</strong> concentration.3 Agitation was vigorous compared to all other experiments.4 HNO3 was added as 50wt% in H2SO4.[0157] It can be seen that despite the various conditions attempted, the amount of starting <strong>[13614-98-7]minocycline</strong> was present in an amount less than 10% and under certain conditions, was substantially removed.Example 2[0158] Experiments were also performed that modified the nitration reaction, the reaction quench, and work up of the nitration reaction. The EPO <DP n="49"/>experiments were conducted using the procedure outlined in Comparative Example 2, modifying the following variables: nitric acid addition time; reaction temperature; molar equivalents of nitric acid (relative to <strong>[13614-98-7]minocycline</strong> HCI); temperature of the quench; composition of the quench solution; addition time of the reaction mixture to the quench solution; and wash method of the isolated cake. The data are shown in Table 3, below. The sole analytical tool used was HPLC analysis.Table 31 Only the bath temperature was monitored in these reactions due to vessel size.2 When IPA was used as the quench, heptanes were then added to obtain the composition of the original quench mixture.3 Wash method 1 : wet cake was washed on the filter with 4:1 IPA:hep. (vol.). Wash method 2: wet cake was slurried three times with 4:1 lPA:hep. (vol.). Wash method No.2 used 20% more wash solution than method No.1.4 Yield is corrected for strength of the product and starting materi...
52 - 100% Comparative Example 2: Preparation of 9-nitrominocvcline[0150] This Example describes the nitration of <strong>[13614-98-7]minocycline</strong> where the product of the nitration is isolated.[0151] A 2-L multi-neck glass flask was equipped with a mechanical stirrer, thermocouple, liquid addition tube, nitrogen line, and gas outlet to a 30% (wt.) EPO <DP n="46"/>caustic scrubber. The flask was charged with sulfuric acid 66 Be (1 ,507 g, 819 ml_, 15 moles). The solution was cooled to 0 - 2C. Minocycline.HCI (92.7% potency, 311 g, 0.58 moles) was added to the sulfuric acid over 0.7 hours at 0 - 14 C with stirring. After addition, the mixture was stirred at 00C for 0.5 hours to obtain a yellow solution. Nitric acid (95.9% nitrate content, 48 g, 32 ml_, 0.73 moles, 1.25 mol equivalents) was added over 3 hours while keeping the mixture at 0 - 2 0C. The mixture was stirred at 00C for 0.3 hours (dark red/black solution). Analysis (area %) by HPLC showed: 0% <strong>[13614-98-7]minocycline</strong>, 75.6% 9-nitro<strong>[13614-98-7]minocycline</strong>, 8.2% largest single impurity (LSI); relative retention time to <strong>[13614-98-7]minocycline</strong> (RRT) = 2.08.[0152] A 22-L multi-neck glass flask was equipped with a mechanical stirrer, thermocouple, and a condenser with nitrogen protection. The flask was charged with 6,704 g (8,540 mL) of isopropanol (IPA) and 1 ,026 g (1 ,500 mL) of heptanes. The solution was then cooled to 0 - 5C. The 9-nitro<strong>[13614-98-7]minocycline</strong> reaction mixture was transferred to the 22-L flask over 2 hours at 0 - 39 C to yield a yellow slurry. The slurry temperature was maintained at 34 - 39C for 2 hours then cooled to 20 - 34C and stirred at 20 - 34 0C for 14.6 hours.[0153] A solution of isopropanol 3,028 g (3,857 mL) and heptanes 660 g (965 mL) was prepared and maintained at 20 - 25C (4:1 , IPA:heptanes by volume). The slurry was filtered on a 30-cm diameter Bchner funnel using No.1 Whatman filter paper under vacuum and nitrogen protection. The resulting wet cake was transferred to a 4-L glass Erlenmeyer flask, equipped with a mechanical stirrer and nitrogen protection. The cake was slurried by adding 1 ,608 mL of the prepared IPA/heptanes solution for 0.5 hours at 23 - 260C.[0154] The slurry was filtered again as described above. The wet cake was reslurried two more times as above (total of three reslurries). After the last filtration, the cake was maintained under vacuum under nitrogen protection for 0.2 hours. The product was dried at 400C under 23 - 11 mmHg of vacuum for 48 hours to a loss on drying (LOD, 8O0C, 1 hour, > 49 mmHg vacuum) value of 1.54. The weight of 9-nitro<strong>[13614-98-7]minocycline</strong> sulfate obtained was 380.1Og, HPLC strength = 76.3% (as the disulfate salt), total impurities = 34.6%, largest single impurity (LSI) 9.46% (RRT = 0.94). Yield from <strong>[13614-98-7]minocycline</strong>.HCI = 86%. Yield corrected for strength of product and starting material = 71%. EPO <DP n="47"/>[0155] It can be seen that isolating the 9-nitro<strong>[13614-98-7]minocycline</strong> compound resulted in a product having a large percentage of impurities.Example 1[0156] Table 2 below outlines nitration experiments conducted using the procedure outlined in Comparative Example 2, where the following variables were modified: nitric acid addition time; reaction temperature; molar equivalents of nitric acid (relative to <strong>[13614-98-7]minocycline</strong> HCI); and agitation rate. In accordance with the methods disclosed herein, none of these reactions were quenched or worked up to isolate product. The sole analytical tool used was HPLC analysis. EPO <DP n="48"/>Table 21 Only the bath temperature was monitored in these reactions due to vessel size.2 Reaction was at 50wt% of original <strong>[13614-98-7]minocycline</strong> concentration.3 Agitation was vigorous compared to all other experiments.4 HNO3 was added as 50wt% in H2SO4.[0157] It can be seen that despite the various conditions attempted, the amount of starting <strong>[13614-98-7]minocycline</strong> was present in an amount less than 10% and under certain conditions, was substantially removed.Example 2[0158] Experiments were also performed that modified the nitration reaction, the reaction quench, and work up of the nitration reaction. The EPO <DP n="49"/>experiments were conducted using the procedure outlined in Comparative Example 2, modifying the following variables: nitric acid addition time; reaction temperature; molar equivalents of nitric acid (relative to <strong>[13614-98-7]minocycline</strong> HCI); temperature of the quench; composition of the quench solution; addition time of the reaction mixture to the quench solution; and wash method of the isolated cake. The data are shown in Table 3, below. The sole analytical tool used was HPLC analysis.Table 31 Only the bath temperature was monitored in these reactions due to vessel size.2 When IPA was used as the quench, heptanes were then added to obtain the composition of the original quench mixture.3 Wash method 1 : wet cake was washed on the filter with 4:1 IPA:hep. (vol.). Wash method 2: wet cake was slurried three times with 4:1 IPA:hep. (vol.). Wash method No.2 used 20% more wash solution than method No.1.4 Yield is corrected for strength of the product and starting material...
52 - 100% Comparative Example 1 : Preparation of 9-nitrominocvcline[0145] This Example describes the nitration of <strong>[13614-98-7]minocycline</strong> where the product of the nitration was isolated.[0146] 13.44 grams of <strong>[13614-98-7]minocycline</strong> p-chlorobenzenesulfonate (i.e., [4S- (4alpha, 12aalpha)]-4,7-bis(dimethylamino)-1 ,4,4a,5,5a,6, 11 , 12a-octahydro- 3,10,12,12a-tetrahydroxy-1 , 11 -dioxo-2-naphthacenecarboxamide p- chlorobenzenesulfonate) was added slowly with stirring to 50 mL of concentrated EPO <DP n="45"/>sulfuric acid. The solution was cooled to 0-150C. Nitric acid (90%, 0.6 ml_) was added slowly and the solution was stirred at 0-150C for 1 - 2 h until the reaction was complete, as determined by HPLC. The solution containing the intermediate 9-nitro<strong>[13614-98-7]minocycline</strong> sulfate (i.e., [4S-(4alpha,12aalpha)-9-nitro]-4,7- bis(dimethylamino)-1 ,4,4a,5,5a,6,1 1 ,12a-octahydro-3,10,12,12a-tetrahydroxy- 1 ,1 i -dioxo-2-naphthacenecarboxamide sulfate) was transferred with stirring to 300 g of ice and water over 20 min. The pH of the quench was adjusted to 5.0-5.5 with 28% aqueous ammonium hydroxide while maintaining the temperature between 0-80C. The precipitate was filtered and washed with water (2 x 10 ml_). The solid was dried under vacuum under a stream of nitrogen to give 9 g of crude 9-nitro<strong>[13614-98-7]minocycline</strong> sulfate.[0147] Analysis (area %) by HPLC showed a purity of 90% with a C4- epirer content of 1.5%. MS(FAB): m/z 503 (M+H), 502 (M+). The product was isolated by precipitation at its isoelectric point from an aqueous solution. The crude sulfate molar yield was 45%.[0148] Table 1 below lists data for other nitration processes:Table 1[0149] It can be seen that isolation of the 9-nitro<strong>[13614-98-7]minocycline</strong> resulted in a high amount of impurities.
52 - 100% This Example describes the nitration of <strong>[13614-98-7]minocycline</strong> where the product of the nitration is isolated.[0151] A 2-L multi-neck glass flask was equipped with a mechanical stirrer, thermocouple, liquid addition tube, nitrogen line, and gas outlet to a 30% (wt.) caustic scrubber. The flask was charged with sulfuric acid 66 Be (1 ,507 g, 819 ml_, 15 moles). The solution was cooled to 0 - 2C. Minocycline. HCI (92.7% potency, 311 g, 0.58 moles) was added to the sulfuric acid over 0.7 hours at 0 - 14 0C with stirring. After addition, the mixture was stirred at 00C for 0.5 hours to obtain a yellow solution. Nitric acid (95.9% nitrate content, 48 g, 32 ml_, 0.73 moles, 1.25 mol equivalents) was added over 3 hours while keeping the mixture at 0 - 2 C. The mixture was stirred at 00C for 0.3 hours (dark red/black solution). Analysis (area %) by HPLC showed: 0% <strong>[13614-98-7]minocycline</strong>, 75.6% 9-nitro<strong>[13614-98-7]minocycline</strong>, 8.2% largest single impurity (LSI); relative retention time to <strong>[13614-98-7]minocycline</strong> (RRT) = 2.08.[0152] A 22-L multi-neck glass flask was equipped with a mechanical stirrer, thermocouple, and a condenser with nitrogen protection. The flask was charged with 6,704 g (8,540 mL) of isopropanol (IPA) and 1 ,026 g (1 ,500 mL) of heptanes. The solution was then cooled to 0 - 5C. The 9-nitro<strong>[13614-98-7]minocycline</strong> reaction mixture was transferred to the 22-L flask over 2 hours at 0 - 39 0C to yield a yellow slurry. The slurry temperature was maintained at 34 - 39C for 2 hours then cooled to 20 - 340C and stirred at 20 - 34 0C for 14.6 hours.[0153] A solution of isopropanol 3,028 g (3,857 mL) and heptanes 660 g (965 mL) was prepared and maintained at 20 - 250C (4:1 , 1 PA: heptanes by volume). The slurry was filtered on a 30-cm diameter Bchner funnel using No.1 Whatman filter paper under vacuum and nitrogen protection. The resulting wet cake was transferred to a 4-L glass Erlenmeyer flask, equipped with a mechanical EPO <DP n="48"/>stirrer and nitrogen protection. The cake was slurried by adding 1 ,608 ml_ of the prepared IPA/heptanes solution for 0.5 hours at 23 - 26C.[0154] The slurry was filtered again as described above. The wet cake was reslurried two more times as above (total of three reslurries). After the last filtration, the cake was maintained under vacuum under nitrogen protection for 0.2 hours. The product was dried at 400C under 23 - 11 mmHg of vacuum for 48 hours to a loss on drying (LOD, 800C, 1 hour, > 49 mmHg vacuum) value of 1.54. The weight of 9-nitro<strong>[13614-98-7]minocycline</strong> sulfate obtained was 380.1Og, HPLC strength = 76.3% (as the disulfate salt), total impurities = 34.6%, largest single impurity (LSI) 9.46% (RRT = 0.94). Yield from <strong>[13614-98-7]minocycline</strong>.HCI = 86%. Yield corrected for strength of product and starting material = 71%.[0155] It can be seen that isolating the 9-nitro<strong>[13614-98-7]minocycline</strong> compound resulted in a product having a large percentage of impurities.; Example 1[0156] Table 2 below outlines nitration experiments conducted using the procedure outlined in Comparative Example 2, where the following variables were modified: nitric acid addition time; reaction temperature; molar equivalents of nitric acid (relative to <strong>[13614-98-7]minocycline</strong> HCI); and agitation rate. In accordance with the methods disclosed herein, none of these reactions were quenched or worked up to isolate product. The sole analytical tool used was HPLC analysis.; Example 2[0158] Experiments were also performed that modified the nitration reaction, the reaction quench, and work up of the nitration reaction. The EPO <DP n="50"/>experiments were conducted using the procedure outlined in Comparative Example 2, modifying the following variables: nitric acid addition time; reaction temperature; molar equivalents of nitric acid (relative to <strong>[13614-98-7]minocycline</strong> HCI); temperature of the quench; composition of the quench solution; addition time of the reaction mixture to the quench solution; and wash method of the isolated cake. The data are shown in Table 3, below. The sole analytical tool used was HPLC analysis.; Comparative Example 1[0172] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was isolated.[0173] 52.0 kg of <strong>[13614-98-7]minocycline</strong>. HCI (92.4% potency) was charged to 4.8 parts (251 kg) sulfuric acid 66 Be at 0 to 150C in a 300 gallon vessel and stirred to effect removal of HCI. 7.48 kg of nitric acid, fuming 100% (95.9% nitrate content, 1.26 equivalents) was charged over 3 hours and 20 minutes.[0174] HPLC analysis indicated >1 % <strong>[13614-98-7]minocycline</strong> remained. Accordingly, 0.31 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.05 equivalents) was added. HPLC analysis still indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Another 0.74 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.12 equivalents) was added. As HPLC testing once again indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 1.11 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.19 equivalents) was added, after which <1% <strong>[13614-98-7]minocycline</strong> remained.[0175] The nitration reaction mixture was transferred to a solution of 21.5 p...
Comparative Example 1[0172] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was isolated.[0173] 52.0 kg of <strong>[13614-98-7]minocycline</strong>.HCI (92.4% potency) was charged to 4.8 parts (251 kg) sulfuric acid 66 Be at 0 to 15C in a 300 gallon vessel and stirred to effect removal of HCI. 7.48 kg of nitric acid, fuming 100% (95.9% nitrate content, 1.26 equivalents) was charged over 3 hours and 20 minutes.[0174] HPLC analysis indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Accordingly, 0.31 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.05 equivalents) was added. HPLC analysis still indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Another 0.74 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.12 equivalents) was added. As HPLC testing once again indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 1.11 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.19 equivalents) was added, after which <1 % <strong>[13614-98-7]minocycline</strong> remained.[0175] The nitration reaction mixture was transferred to a solution of 21.5 parts IPA / 3.3 parts heptane (1120 kg IPA / 171 kg heptane) at 0 to 36 0C. The slurry was filtered (lengthy filtration time), washed with IPA/heptane 4:1 and dried at NMT 400C to an LOD of NMT 6%, yielding 70.9 kg of sulfate salt (97% crude yield) for use in reduction reaction.; Comparative Example 2[0180] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was isolated.[0181] 104 kg <strong>[13614-98-7]minocycline</strong>.HCI (90.3% potency) charged to 4.8 parts (502 kg) sulfuric acid 66Be at 0 - 100C in a 300 gallon vessel and stirred to effect removal of HCI. 15.2 kg fuming nitric acid (100.4%, 1.25 equivalents) charged over 3 hours at 0 - 6C, 100 rpm. As HPLC testing indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.69 kg fuming nitric acid (100.4%, 0.06 equivalents), was added, after which <strong>[13614-98-7]minocycline</strong> <1%. The nitration mixture was transferred to a solution of 21.5 parts IPA / 3.3 part heptane at 0-360C.[0182] The slurry was filtered (lengthy filtration time), washed with IPA/heptane 4:1 and dried at NMT 40C to an LOD of NMT 6%, yielding 140 kg of sulfate salt (95% crude yield) for use in reduction reaction.Example 4[0183] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was not isolated. EPO <DP n="54"/>[0184] 104 kg <strong>[13614-98-7]minocycline</strong> HCI (90% potency) charged to 7.3 parts (763 kg) sulfuric acid 660Be at 5-15C and stirred to effect removal of HCI. 14.9 kg fuming nitric acid (100%, 1.25 equivalents) was charged over 1 hour at 5-15C, 120 rpm. As HPLC anlysis indicated that >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.69 kg fuming nitric acid (100%, 0.06 equivalents), was added after which <strong>[13614-98-7]minocycline</strong>[0185] The nitration mixture was transferred to 4.2 parts (440 kg) methanol at -10 to -200C. The quenched batch was adjusted to 4 - 1O0C and used as is in the reduction reaction.
Example 3[0176] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was not isolated. EPO <DP n="53"/>[0177] 25.0 kg of <strong>[13614-98-7]minocycline</strong>.HCI (94.4% potency) was charged to 7.3 parts (183 kg) sulfuric acid 66 Be at 5 to 15 0C in a 100 gallon vessel and stirred to effect removal of HCI. 2.5015 kg of nitric acid, 85% (86.6% nitrate content, 1.25 equivalents) was added to the vessel over 78 minutes at 9 to 15C.[0178] HPLC analysis indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Another 0.261 kg nitric acid, 85% (86.6% nitrate content, 0.13 equivalents) was added. As HPLC once again indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.261 kg nitric acid, 85% (86.6% nitrate content, 0.13 equivalents) was added. As HPLC still indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.174 kg nitric acid, 85% (86.6% nitrate content, 0.09 equivalents) was added, after which it appeared the reaction reached a plateau at 1.7% <strong>[13614-98-7]minocycline</strong> starting material.[0179] The nitration reaction mixture was transferred to 4.2 parts (106 kg) methanol at -20 to 100C. The quenched batch was adjusted to 4 to 100C and used as-is in the reduction reaction.
Comparative Example 1[0172] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was isolated.[0173] 52.0 kg of <strong>[13614-98-7]minocycline</strong>. HCI (92.4% potency) was charged to 4.8 parts (251 kg) sulfuric acid 66 Be at 0 to 150C in a 300 gallon vessel and stirred to effect removal of HCI. 7.48 kg of nitric acid, fuming 100% (95.9% nitrate content, 1.26 equivalents) was charged over 3 hours and 20 minutes.[0174] HPLC analysis indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Accordingly, 0.31 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.05 equivalents) was added. HPLC analysis still indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Another 0.74 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.12 equivalents) was added. As HPLC testing once again indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 1.11 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.19 equivalents) was added, after which <1% <strong>[13614-98-7]minocycline</strong> remained.[0175] The nitration reaction mixture was transferred to a solution of 21.5 parts IPA / 3.3 parts heptane (1120 kg IPA / 171 kg heptane) at 0 to 36 C. The slurry was filtered (lengthy filtration time), washed with IPA/heptane 4:1 and dried at NMT 400C to an LOD of NMT 6%, yielding 70.9 kg of sulfate salt (97% crude yield) for use in reduction reaction.; Comparative Example 2[0180] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was isolated.[0181] 104 kg <strong>[13614-98-7]minocycline</strong>.HCI (90.3% potency) charged to 4.8 parts (502 kg) sulfuric acid 66Be at 0 - 100C in a 300 gallon vessel and stirred to effect removal of HCI. 15.2 kg fuming nitric acid (100.4%, 1.25 equivalents) charged over 3 hours at 0 - 6C, 100 rpm. As HPLC testing indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.69 kg fuming nitric acid (100.4%, 0.06 equivalents), was added, after which <strong>[13614-98-7]minocycline</strong> <1%. The nitration mixture was transferred to a solution of 21.5 parts IPA / 3.3 part heptane at 0-360C.[0182] The slurry was filtered (lengthy filtration time), washed with IPA/heptane 4:1 and dried at NMT 400C to an LOD of NMT 6%, yielding 140 kg of sulfate salt (95% crude yield) for use in reduction reaction.Example 4[0183] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was not isolated. EPO <DP n="54"/>[0184] 104 kg <strong>[13614-98-7]minocycline</strong> HCI (90% potency) charged to 7.3 parts (763 kg) sulfuric acid 66 Be at 5-15C and stirred to effect removal of HCI. 14.9 kg fuming nitric acid (100%, 1.25 equivalents) was charged over 1 hour at 5-150C, 120 rpm. As HPLC anlysis indicated that >1 % <strong>[13614-98-7]minocycline</strong> remained, another 0.69 kg fuming nitric acid (100%, 0.06 equivalents), was added after which <strong>[13614-98-7]minocycline</strong>[0185] The nitration mixture was transferred to 4.2 parts (440 kg) methanol at -10 to -2O0C. The quenched batch was adjusted to 4 - 100C and used as is in the reduction reaction.
Example 3[0176] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was not isolated. EPO <DP n="53"/>[0177] 25.0 kg of <strong>[13614-98-7]minocycline</strong>.HCI (94.4% potency) was charged to 7.3 parts (183 kg) sulfuric acid 66 Be at 5 to 15 0C in a 100 gallon vessel and stirred to effect removal of HCI. 2.5015 kg of nitric acid, 85% (86.6% nitrate content, 1.25 equivalents) was added to the vessel over 78 minutes at 9 to 150C.[0178] HPLC analysis indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Another 0.261 kg nitric acid, 85% (86.6% nitrate content, 0.13 equivalents) was added. As HPLC once again indicated >1 % <strong>[13614-98-7]minocycline</strong> remained, another 0.261 kg nitric acid, 85% (86.6% nitrate content, 0.13 equivalents) was added. As HPLC still indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.174 kg nitric acid, 85% (86.6% nitrate content, 0.09 equivalents) was added, after which it appeared the reaction reached a plateau at 1.7% <strong>[13614-98-7]minocycline</strong> starting material.[0179] The nitration reaction mixture was transferred to 4.2 parts methanol (106 kg) at -20 to 100C. The quenched batch was adjusted to 4 to 100C and used as-is in the reduction reaction.
Comparative Example 1[0172] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was isolated.[0173] 52.0 kg of <strong>[13614-98-7]minocycline</strong>.HCI (92.4% potency) was charged to 4.8 parts (251 kg) sulfuric acid 66 Be at 0 to 15C in a 300 gallon vessel and stirred to effect removal of HCI. 7.48 kg of nitric acid, fuming 100% (95.9% nitrate content, 1.26 equivalents) was charged over 3 hours and 20 minutes.[0174] HPLC analysis indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Accordingly, 0.31 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.05 equivalents) was added. HPLC analysis still indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Another 0.74 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.12 equivalents) was added. As HPLC testing once again indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 1.11 kg of nitric acid, fuming 100% (95.5% nitrate content, 0.19 equivalents) was added, after which <1 % <strong>[13614-98-7]minocycline</strong> remained.[0175] The nitration reaction mixture was transferred to a solution of 21.5 parts IPA / 3.3 parts heptane (1120 kg IPA / 171 kg heptane) at 0 to 36 C. The slurry was filtered (lengthy filtration time), washed with IPA/heptane 4:1 and dried at NMT 400C to an LOD of NMT 6%, yielding 70.9 kg of sulfate salt (97% crude yield) for use in reduction reaction.; Comparative Example 2[0180] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was isolated.[0181] 104 kg <strong>[13614-98-7]minocycline</strong>.HCI (90.3% potency) charged to 4.8 parts (502 kg) sulfuric acid 660Be at 0 - 100C in a 300 gallon vessel and stirred to effect removal of HCI. 15.2 kg fuming nitric acid (100.4%, 1.25 equivalents) charged over 3 hours at 0 - 6C, 100 rpm. As HPLC testing indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.69 kg fuming nitric acid (100.4%, 0.06 equivalents), was added, after which <strong>[13614-98-7]minocycline</strong> <1%. The nitration mixture was transferred to a solution of 21.5 parts IPA / 3.3 part heptane at 0-360C.[0182] The slurry was filtered (lengthy filtration time), washed with IPA/heptane 4:1 and dried at NMT 40C to an LOD of NMJ 6%, yielding 140 kg of sulfate salt (95% crude yield) for use in reduction reaction.Example 4[0183] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was not isolated. EPO <DP n="54"/>[0184] 104 kg <strong>[13614-98-7]minocycline</strong> HCI (90% potency) charged to 7.3 parts (763 kg)sulfuric acid 660Be at 5-15C and stirred to effect removal of HCI. 14.9 kg fuming nitric acid (100%, 1.25 equivalents) was charged over 1 hour at 5-15C, 120 rpm. As HPLC anlysis indicated that >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.69 kg fuming nitric acid (100%, 0.06 equivalents), was added after which <strong>[13614-98-7]minocycline</strong> <1%.[0185] The nitration mixture was transferred to 4.2 parts (440 kg) methanol at -10 to -2O0C. The quenched batch was adjusted to 4 - 1O0C and used as is in the reduction reaction.
Example 3[0176] This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was not isolated. EPO <DP n="53"/>[0177] 25.0 kg of <strong>[13614-98-7]minocycline</strong>.HCI (94.4% potency) was charged to 7.3 parts (183 kg)sulfuric acid 66 Be at 5 to 15 C in a 100 gallon vessel and stirred to effect removal of HCI. 2.5015 kg of nitric acid, 85% (86.6% nitrate content, 1.25 equivalents) was added to the vessel over 78 minutes at 9 to 15C.[0178] HPLC analysis indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Another 0.261 kg nitric acid, 85% (86.6% nitrate content, 0.13 equivalents) was added. As HPLC once again indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.261 kg nitric acid, 85% (86.6% nitrate content, 0.13 equivalents) was added. As HPLC still indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.174 kg nitric acid, 85% (86.6% nitrate content, 0.09 equivalents) was added, after which it appeared the reaction reached a plateau at 1.7% <strong>[13614-98-7]minocycline</strong> starting material.[0179] The nitration reaction mixture was transferred to 4.2 parts (106 kg) methanol at -20 to 1O0C. The quenched batch was adjusted to 4 to 100C and used as-is in the reduction reaction.
This Example describes a hydrogenation reaction where the 9- nitro<strong>[13614-98-7]minocycline</strong> intermediate was not isolated. EPO <DP n="54"/>[0177] 25.0 kg of <strong>[13614-98-7]minocycline</strong>.HCI (94.4% potency) was charged to 7.3 parts (183 kg) sulfuric acid 66 Be at 5 to 15 C in a 100 gallon vessel and stirred to effect removal of HCI. 2.5015 kg of nitric acid, 85% (86.6% nitrate content, 1.25 equivalents) was added to the vessel over 78 minutes at 9 to 15C.[0178] HPLC analysis indicated >1% <strong>[13614-98-7]minocycline</strong> remained. Another 0.261 kg nitric acid, 85% (86.6% nitrate content, 0.13 equivalents) was added. As HPLC once again indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.261 kg nitric acid, 85% (86.6% nitrate content, 0.13 equivalents) was added. As HPLC still indicated >1% <strong>[13614-98-7]minocycline</strong> remained, another 0.174 kg nitric acid, 85% (86.6% nitrate content, 0.09 equivalents) was added, after which it appeared the reaction reached a plateau at 1.7% <strong>[13614-98-7]minocycline</strong> starting material.[0179] The nitration reaction mixture was transferred to 4.2 parts (106 kg) methanol at -20 to 10C. The quenched batch was adjusted to 4 to 10C and used as-is in the reduction reaction.

  • 3
  • [ 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 [ No CAS ]
  • [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 [ No CAS ]
  • 4
  • [ 13614-98-7 ]
  • [ 153621-82-0 ]
  • 5
  • [ 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 [ No CAS ]
YieldReaction ConditionsOperation in experiment
a) Preparation of 9-aminominocvcline disulphate from Minocycline hydrochloride; Dry nitrogen gas was purged through concentrated sulphuric acid (450 ml) at 28+/-2C, and it was cooled to -50C to 00C. Minocycline hydrochloride (150 g) was added portion-wise to the sulphuric acid while controlling temperature below -1C under stirring (exothermic reaction observed). After complete addition of <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong>, the solution was stirred for 15-20 minutes at below -1C. Potassium nitrate (38.4 g) was added portion-wise to the solution while controlling temperature below -1C under stirring (Exothermic reaction was observed). The reaction mixture obtained was stirred for 1-2 hours at -50C.In a flask, de-ionized water (420 ml) having dissolved oxygen content below 10 ppm, methanol (200 ml) and diisopropyl ether (750 ml) were added and cooled to -30C to -25C. The reaction mixture obtained above was added to the flask by controlling temperature below 15C (exothermic reaction was observed). The resultant mixture in the flask was washed with de-ionized water (105 ml). The mixture was stirred for 10-15 minutes below 15C and then it was allowed to stand for 20-30 minutes. The product enriched aqueous layer was separated. To the separated aqueous layer, activated carbon (20 gm) was added followed by stirring for 20-30 minutes. The aqueous layer was filtered through hyfio bed followed by washing of the bed with methanol (200 ml) at 20-300C under nitrogen. The filtrate obtained was transferred to parr apparatus bottle for hydrogenation. To the filtrate, 10% Pd/C (3.0 g; 50% wet) was added and it was flushed twice with nitrogen, once with hydrogen and finally hydrogen pressure of around 50 psi was applied to it. It was maintained for 2-5 hours at 20-250C. The resultant mixture was filtered through hyflo bed followed by washing with methanol (200 ml) at 20-300C under nitrogen. b) Preparation of granular 9-amino<strong>[13614-98-7]minocycline</strong> disulphate and crystallization thereofIn another flask containing isopropyl alcohol (5.25 L) at 20-300C, the filtrate obtained (from step a) was dispersed for precipitation at 25+/-2C in 30-60 minutes. When granules formation was observed, isopropyl alcohol (4.5 L) was added to it simultaneously. This was stirred for 1 hour and simultaneously cooled to 0-50C. It was filtered under nitrogen pressure using sintered funnel at 20-300C to obtain cake of 9-amino<strong>[13614-98-7]minocycline</strong> disulphate.
  • 6
  • [ 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 [ No CAS ]
  • 7
  • [ 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 [ No CAS ]
  • 8
  • [ 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 [ No CAS ]
  • 9
  • [ 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 [ No CAS ]
  • (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 [ No CAS ]
YieldReaction ConditionsOperation in experiment
[5S- (5a, 5aa, 6aa, 12ba, 12ca) J-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 [dejnaphthacene-3-carboxylic acid amide and [6S-(2ba, 6a, 6aa, 7aa)]-6, 9-bis (dimethylamino)-1, 2b, 3,6, 6a, 7,7a, 8-octahydro- 2b, 5, 12-trihydroxy-3-oxo1,2-diaza-cyclopenta[fg]naphthacene-4-carboxylic acid amide.; Minocycline hydrochloride (0.050 g, 0.10 mmol) was suspended in water (1.25 mL). Hydrazine hydrate (0.0175 mL, 0.36 mmol) was then added and the reaction mixture was stirred at room temperature overnight under nitrogen. After the solvent had been removed by freeze-drying, the crude product was separated using a C18-reverse phase Vydac column (50 x 250 mm). By applying a binary gradient of 0. 1% TFA in water (phase A) and 0. 1% TFA in acetonitrile (phase B) on a gradient from 0% phase B to 5% phase B in 100 min at a flow rate of 20 mL/min, [5S- (5a, 5aa, 6aa, 12ba, 12ca)]-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 separated as a trifluoroacetate. [6S- (2ba, 6a, 6aa, 7aa) ] -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 eluted soon afterwards under isocratic conditions (95% phase A, 5% phase B, 20 mL/min). After freeze-drying the collected fractions, the solid materials were dissolved in the minimum amount of water and treated with the required amount of triethylamine. The tetracycline derivatives were separated from the water-soluble salts using PrepSepC18 disposable extraction columns. [5S- (5a, 5aa, 6aa, 12ba, 12ca)]-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. Rt (method A) = 2.8 min. ESI-MS m/z (M + H) 472. 2.'H NMR (D20) 8 1.55 (q, 1 H, J = 12.7 Hz), 2.22 (d, 1 H, J = 10.9 Hz), 2.47 (m, 1 H), 2.74 (dd, 1 H, J = 13. 0 and 15.3 Hz), 2.87 (m, 1H), 3.02 (s, 6H), 3.03 (m, 1H), 3.19 (d, 1H, J = 13. 6 Hz), 3.28 (s, 6H), 3.86 (s, 1 H), 7.12 (d, 1 H, J = 9.1 Hz), 7.91 (d, 1 H, J = 9. 1 Hz). [6S- (2ba, 6a, 6aa, 7aa)]-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. Rt (method A) = 4.0 min. ESI-MS m/z (M + H) 454. 2.'H NMR (D20) 8 1. 53 (q, 1H, J = 11.5 Hz), 2.12 (t, 1H, J= 15. 1 Hz), 2.24 (d, 1H, J= 11.4 Hz), 2. 96 (s, 6H), 3.06 (m, 2H), 3.20 (bs, 7H), 3.95 (s, 1 H), 6.93 (d, 1 H, J = 8. 9 Hz), 7.42 (d, 1 H, J = 8. 9 Hz).
  • 10
  • [ 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 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With ammonia; In ethanol; at 20℃; for 4h;Heating / reflux; [4S- (4a, 12aa) j-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.; Minocycline hydrochloride (100 mg, 0.20 mmol) was dissolved in absolute ethanol (20 mL). Ammonia gas was bubbled into the solution under refluxed for 2 h, then the reaction mixture was further stirred at room temperature for 2 h under nitrogen. The reaction mixture was then evaporated to dryness, water (5.0 mL) was added, and the solid material was filtered off. The filtrate was extracted with dichloromethane (3 x 5 mL), the organic phase was dried over anhydrous sodium sulfate, and treated with hexane (15 mL) prior to leaving it at-20C for 1 h. The precipitated material was filtered off, and the filtrate was evaporated to dryness to give, after crystallization from ethanol-hexane, the [4S- (4a, 12aa)]-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 as pale yellowish powder. Rt (method A) = 4.8 min. ESI-MS m/z (M + H) 456. 9.'H NMR (D20) 8 1.63 (q, 1 H, J = 13.0 Hz), 2.14 (d, 1 H, J = 13.4 Hz), 2.19 (t, 1 H, J = 14.5 Hz), 2.58 (s, 6H), 2.69 (d, 1 H, J = 12.2 Hz), 2.75-2. 95 (m, 1H), 2.85 (s, 6H), 2.98 (d, 1 H, J = 15.1 Hz), 3.73 (s, 1 H), 6.80 (d, 1 H, J = 8.7 Hz), 7.35 (d, 1 H, J = 8.7 Hz).
YieldReaction ConditionsOperation in experiment
EXAMPLE 4 Conversion of Minocycline Hydrochloride Calcium Chloride Complex to Minocycline Hydrochloride In 15.1 ml. of 1N hydrochloric acid there was dissolved 7.56 g. of minocycline hydrochloride calcium chloride complex (assaying 730.4 mcg./mg. as minocycline neutral and containing 1.565% calcium) followed by 484 mg. of oxalic acid dihydrate. The pH of the mixture was adjusted to 1.9 with 5N sodium hydroxide and there was added thereto 80 mg. of Darco G-60. The suspension was stirred 2 hours at 5 C., filtered through Celite and the cake washed with 5.8 ml. of 5% sodium chloride solution. The pH of the combined filtrate and wash was adjusted to 4.0 with 5N sodium hydroxide and the resultant suspension of minocycline hydrochloride crystals was aged 1 hour at room temperature and overnight at 5 C. The product was filtered off and washed with 3.8 ml. of 5% sodium chloride solution. The wet crystals were redissolved in 5.12 ml. of a solution prepared by mixing 4.8 ml. of concentrated hydrochloric acid with 29 ml. of water, treated 15 minutes with 90 mg. of Darco G-60 and filtered through Celite. The filter cake was washed with 1.91 ml. of water and the pH of the combined filtrate and wash was adjusted to 4.0 with 5N sodium hydroxide. After aging overnight at 5 C. the product was filtered off, washed with 5.8 ml. of water and dried at 40 C. in vacuo. There was thus obtained 4.28 g. (68.8%) of minocycline hydrochloride assaying 887.1 mcg./mg. as minocycline neutral containing 11.6 mcg./mg. epi minocycline.
  • 12
  • [ 13614-98-7 ]
  • [ 149934-16-7 ]
YieldReaction ConditionsOperation in experiment
93% To further validate our process, we performed the nitration reaction under the same scaled-down conditions described above using <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> from commercial sources. Based on scientific data gathered from previous reactions, we modified slightly the HCl removal protocol. The procedure was simplified by applying vacuum at 50 torr for up to 3 hr before nitration. A summary of the chloride content at several times before nitration is presented in Table 16. TABLE 16 CHLORIDE CONTENT OF MINOCYCLINE IN SULFURIC ACID Sampling point Chloride content (ppm) Before vacuum 1526 After vacuum at 50 51 torr for 1 hr After vacuum at 50 <50* torr for 2 hr After vacuum at 50 <50 torr for 3 hr After no vacuum, 201¥ o/n,§ 50 rpm *reporting limit: 50 ppm; §o/n = overnight; ¥accuracy of +/- 100 ppm.The chloride content, after holding overnight at 5 C. with no vacuum was 201 ppm owing to the accuracy (+/-100 ppm) of the determinations. The nitration reaction was completed using 1.2 eq nitric acid. During the addition of nitric acid over 100 min, the batch temperature was maintained at 6 C. while the jacket set temperature was at 10 C. It is interesting to note that when 1.0 eq of nitric acid was added based on volume, the batch temperature started to decrease which was indicative of the end of the reaction exotherm. Following precipitation from IPA:heptane and filtration, 9-nitro<strong>[13614-98-7]minocycline</strong> was obtained in 93% yield (<strong>[13614-98-7]minocycline</strong> less than 1%).The purity profile presented in Table 15 was very similar to the first 500 g batch described above.
With sulfuric acid; potassium nitrate; at 0 - 5℃; for 2h;Product distribution / selectivity; Minocycline hydrochloride (5 g) was completely dissolved in H2SO4 98% (30 ml), whereupon the mixture was cooled to about 0 C.-5 C. and solid KNO3 (1.22 g, 1.2 eq.) was charged into the solution. When the reaction was completed (as determined by HPLC), cold iso-propanol was added dropwise, under cooling at 0 C.-5 C., until a precipitate started to form. The remaining solvent was run continuously into the suspension (total amount of IPA was about 380 ml). The resulting suspension was stirred overnight and filtered under nitrogen in such manner that when all the filtrate was passed through the funnel, the vacuum was disconnected and the solid was further dried in the nitrogen stream. If suitable equipment is available, the filtration can alternatively be performed under nitrogen pressure, i.e. similarly to a common industrial method of filtration. The initially dried material was further dried in a vacuum oven at about 40 C. overnight to afford the desired product as a yellow to brownish solid stable under regular conditions; Example 2-Minocycline hydrochloride (60 gr) was completely dissolved in H2SO4 98% (360 ml), whereupon the mixture was cooled down about 0 C.-5 C. and solid KNO3 (14.1 gr) was introduced into the solution portion-wise during 1.5-2 hours. When the reaction was complete (based on HPLC), cold iso-propanol was added dropwise, under cooling at 0 C.-5 C., until a precipitate started to form. The remaining solvent was then run continuously into the suspension (total amount of IPA is 3000 ml) . The resulting suspension was stirred for 1 hour and filtered under nitrogen in such manner that when all the filtrate was passed through the funnel, the vacuum was disconnected and the solid was further dried in the nitrogen stream. The initially dried material was further dried in a vacuum oven at about 40 C. overnight to afford 79.4 gr of the desired product, which was characterized by chromatographic purity of about 70.6%; Example 3-Minocycline hydrochloride (5 gr) was completely dissolved in H2SO4 98% (30 ml), whereupon the mixture was cooled down to about 0 C. -5 C. and solid KNO3 (1.22 gr) was introduced into the solution. When the reaction was complete, (based on HPLC,) cold iso-propanol was added dropwise, under cooling at 0 C.-5 C., until a precipitate started to form. The remaining solvent was run continuously into the suspension (total amount of IPA is 375ml). The resulting suspension was stirred overnight at ambient temperature, and then filtered and washed twice with about 20 mL portions of IPA under nitrogen. When all the filtrate was passed through the funnel, the vacuum was disconnected and the solid was further dried in the nitrogen stream. The initially dried material was further dried in a vacuum oven at about 40 C. overnight to afford 7.77 gr of the desired product, which was characterized by chromatographic purity of about 77%.
With sulfuric acid; nitric acid; In water; for 0.5 - 6h;Product distribution / selectivity; The impurity profile of 9-nitrominocyline produced in the nitration reaction, using <strong>[13614-98-7]minocycline</strong> sulfate vs. <strong>[13614-98-7]minocycline</strong> HCl was examined and the purity data is shown in Table 2. TABLE 2 PURITY OF 9-NITROMINOCYCLINE PRODUCED FROM MINOCYCLINE Sample type Purity (%) Imp A (%) Imp B (%) Minocycline sulfate 95.3 - - 9-nitro<strong>[13614-98-7]minocycline</strong> from 76.3 <0.1 5.5 <strong>[13614-98-7]minocycline</strong> sulfate 9-nitro<strong>[13614-98-7]minocycline</strong> from 61.6 0.1 8.8 <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> A complete purity profile data table showing all nitration reactions, inclusive of impurities, performed is included in Table 15 hereinbelow.Reaction parameters (<strong>[13614-98-7]minocycline</strong> sulfate): 16.5 g starting material, 50 ml (3 vols) sulfuric acid, 1.18 eq nitric acid, 100 ml 3-neck round-bottom flask (6 cm diameter), 4 cm length impeller. Stirring rate not measured. Nitrogen flow rate not measured.Reaction parameters (<strong>[13614-98-7]minocycline</strong> HCl): 50 g starting material, 150 ml (3 vols) sulfuric acid, 1.53 eq nitric acid, 250 ml multi-neck round bottom flask. Impeller size, stirring rate and nitrogen flow rate not measured. Chloride ion content not measured.A better purity of 9-nitro<strong>[13614-98-7]minocycline</strong> can be obtained if nitration is performed on <strong>[13614-98-7]minocycline</strong> sulfate vs <strong>[13614-98-7]minocycline</strong> HCl. These results substantiate the observation that the presence of HCl has a detrimental effect on the quality of the 9-nitro<strong>[13614-98-7]minocycline</strong> produced. Residual HCl will react with nitric acid thus making the latter inaccessible for nitration as shown in Schemes A and B below; Three experiments were performed to examine the effect of nitric acid addition time on the purity of isolated 9-nitro<strong>[13614-98-7]minocycline</strong>. The experiments were performed on 50 g <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> dissolved in 150 ml sulfuric acid in a 1-L ChemGlass cylindrical reactor (diameter 9.7 cm), impeller diameter 5 cm. The mixing speed was set at 500 rpm. The purity of the product at different addition times is presented in Table 6.In all experiments, the starting material was consumed and the reaction went to completion, with less than 1.0% <strong>[13614-98-7]minocycline</strong> being found. Fast addition of nitric acid resulted in a higher level of 2 impurities (impurity B at rrt 0.59 and rrt 0.68) and a lower purity for 9-nitro<strong>[13614-98-7]minocycline</strong> as compared to the control reaction (Experiment 2). Extended addition of nitric acid did not change the purity profile when compared to the control reaction. The addition time had no significant effect on impurity A levels. The preferred addition time range is 100 min to 180 min. TABLE 6 PURITY OF 9-NITROMINOCYCLINE ON NITRIC ACID ADDITION TIME Purity 9- nitro-mino- Impurity Impurity Impurity Exper- Addition cycline A B (%) B (%) iment time (min) (%) (%) (rrt 0.59) (rrt 0.68) 1 30 55.29 <0.1 11.29 9.90 2 100 70.58 0.11 7.95 6.85 3 360 71.80 <0.1 7.68 6.54
With hydrogenchloride; sulfuric acid; nitric acid; In water; for 1.66667h;Product distribution / selectivity; A more controlled set of experiments to monitor the effect of residual HCl on the purity of 9-nitro<strong>[13614-98-7]minocycline</strong> was conducted. These experiments were performed on 50 g scale in a 1-L ChemGlass cylindrical reactor, impeller diameter 5 cm and mixing rate 500 rpm. Data in Table 3 summarizes the purity of 9-nitro<strong>[13614-98-7]minocycline</strong> obtained at various levels of residual HCl in the starting material mixture just before nitration began. Nitric acid was added over 100 mins from the middle of the reactor vessel.Data shows the purity of 9-nitro<strong>[13614-98-7]minocycline</strong> diminished as residual HCl increased. As HCl is increased to >1000 ppm, the purity dramatically declines. Concurrently, the level of Impurity A also increased as residual HCl increased. These results confirm the detrimental effects of residual HCl has on the nitration reaction. Residual HCl produces high levels of impurity A. However, with the increase in the level of impurity A (up to 10%), little effect on the subsequent hydrogenation in 80:20 water:methanol solvent mixture was noted. TABLE 3 EFFECT OF RESIDUAL HCL ON PURITY OF 9-NITROMINOCYCLINE Purity 9- nitro- Impurity B Impurity Residual <strong>[13614-98-7]minocycline</strong> (%) (rrt B (%) (rrt HCl (ppm) (%) Impurity A (%) 0.59) 0.68) 68 69.12 0.43 8.12 6.33 482 65.91 5.87 7.06 5.22 1332 47.96 23.93 6.70 5.62 Nitration conducted on <strong>[13614-98-7]minocycline</strong> sulfate reached completion with only 1.2eq nitric acid. In control reactions using <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong>, 1.5eq nitric acid was typically required. This can be explained by the low chloride content of <strong>[13614-98-7]minocycline</strong> sulfate (106 ppm). At low concentrations of chloride, nitric acid will be available for nitration and not react with HCl. Dissolved HCl consumes nitric acid to produce nitric oxide and chlorine gas (Scheme A) or nitrosyl chloride (Scheme B). In either path, chlorine gas is produced that can react with <strong>[13614-98-7]minocycline</strong> leading to Impurity A. This leads to the necessity to use excess nitric acid to complete the nitration. These results support the conclusion that residual HCl is a parameter in the nitration step.Scheme A. Reaction of HCl with Nitric Acid (Path 1)2 HNO3+6 HCl?2 NO+3 Cl2+4 H2O Scheme B. Reaction of HCl with Nitric Acid (Path 2)HNO3+3 HCl?NOCl+Cl2+2 H2O

  • 13
  • [ 629-27-6 ]
  • [ 13614-98-7 ]
  • [ 1042222-57-0 ]
  • 14
  • [ 2050-77-3 ]
  • [ 13614-98-7 ]
  • [ 1042222-58-1 ]
  • 15
  • [ 4292-19-7 ]
  • [ 13614-98-7 ]
  • [ 1042222-59-2 ]
  • 16
  • [ 19218-94-1 ]
  • [ 13614-98-7 ]
  • [ 1042222-60-5 ]
  • 17
  • [ 13614-98-7 ]
  • [ 638-45-9 ]
  • [ 1042222-56-9 ]
  • 18
  • [ 1075240-32-2 ]
  • [ 13614-98-7 ]
  • [ 1075240-33-3 ]
  • [ 1075240-34-4 ]
  • 19
  • [ 1075240-32-2 ]
  • [ 13614-98-7 ]
  • C25H31N3O9 [ No CAS ]
  • 20
  • [ 1075240-44-6 ]
  • [ 13614-98-7 ]
  • [ 1075240-36-6 ]
  • [ 1075240-35-5 ]
  • 21
  • [ 1075240-45-7 ]
  • [ 13614-98-7 ]
  • [ 1075240-33-3 ]
  • C31H40Cl2N4O8 [ No CAS ]
  • 22
  • [ 1075240-45-7 ]
  • [ 13614-98-7 ]
  • [ 1075240-40-2 ]
  • 23
  • [ 1075240-46-8 ]
  • [ 13614-98-7 ]
  • [ 1075240-33-3 ]
  • C31H41ClN4O8 [ No CAS ]
  • 24
  • [ 1075240-46-8 ]
  • [ 13614-98-7 ]
  • [ 1075240-41-3 ]
  • 25
  • [ 1075240-46-8 ]
  • [ 13614-98-7 ]
  • C32H43ClN4O9 [ No CAS ]
  • 26
  • [ 1075240-47-9 ]
  • [ 13614-98-7 ]
  • [ 1075240-33-3 ]
  • [ 1075240-37-7 ]
  • 27
  • [ 1075240-47-9 ]
  • [ 13614-98-7 ]
  • [ 1075240-38-8 ]
  • [ 1075240-39-9 ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid; In water; for 0.5 - 3h;nitrogen flow;Conversion of starting material; Generally, nitration may take place by contacting <strong>[13614-98-7]minocycline</strong> or a salt thereof with a reaction medium within a reactor vessel, wherein the reaction medium forms a surface defining a headspace portion above the surface and a subsurface portion beneath the surface, the method comprising (a) sparging the headspace portion without sparging the subsurface portion, (b) sparging the subsurface portion without sparging the headspace portion, or (c) sparging the headspace portion and the subsurface portion.Minocycline is preferably dissolved in the reaction medium. The method may comprise sparging the headspace portion without sparging the subsurface portion; sparging the subsurface portion without sparging the headspace portion; or sparging the headspace portion and the subsurface portion.The salt of <strong>[13614-98-7]minocycline</strong> may be a hydrochloride, wherein sparging decreases the amount of hydrogen chloride in the reactor vessel. Preferably, the amount of hydrogen chloride is decreased by up to 95%.A study was conducted on the effect of inert gas (such as nitrogen) sparging and use of vacuum on gaseous hydrogen chloride removal prior to addition of nitric acid. Reaction parameters set for each experiment were as follows: 40 g <strong>[13614-98-7]minocycline</strong>, multi-neck 250 ml round-bottom flask (diameter 8 cm), impeller length 4 cm, mixing speed 100 rpm (i.e. under poor mixing conditions). The following experiments were performed: 1. Nitrogen sparging in the headspace (50 ml/min); 2. Nitrogen sparging sub-surface (50 ml/min); 3. Vacuum (300 torr); 4. No sparging. Samples of dissolved <strong>[13614-98-7]minocycline</strong> in sulfuric acid at selected times were analyzed for chloride content as shown in Table 4. The chloride content of <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> was 6.8%. TABLE 4 CHLORIDE CONTENT OF MINOCYCLINE IN SULFURIC ACID AT SELECTED TIMES Time (mins) after Time (mins) after Chloride complete Chloride complete dissolution content dissolution of content of <strong>[13614-98-7]minocycline</strong> (ppm)* <strong>[13614-98-7]minocycline</strong> (ppm) Subsurface nitrogen Headspace nitrogen sparging sparging 0 1527 0 1725 30 1515 30 1673 60 1549 60 1941 90 1497 90 1674 180 1282 180 1750 Vacuum No sparging 0 1852 0 2253 30-No. 30 2269 60 1640 60 2224 90 1607 90 2349 *chloride content determined by IC.No.not determined.The experimental data suggests that nitrogen sparging has the ability to remove HCl from the system. Subsurface sparging showed a slightly better ability to remove HCl. Using a vacuum pull (300 torr) was comparable to nitrogen sparging in the headspace.
With sulfuric acid; In water; under 30 - 760.051 Torr; for 0.5 - 3h;Conversion of starting material; Generally, nitration may take place by contacting <strong>[13614-98-7]minocycline</strong> or a salt thereof with a reaction medium within a reactor vessel, wherein the reaction medium forms a surface defining a headspace portion above the surface and a subsurface portion beneath the surface, the method comprising (a) sparging the headspace portion without sparging the subsurface portion, (b) sparging the subsurface portion without sparging the headspace portion, or (c) sparging the headspace portion and the subsurface portion.Minocycline is preferably dissolved in the reaction medium. The method may comprise sparging the headspace portion without sparging the subsurface portion; sparging the subsurface portion without sparging the headspace portion; or sparging the headspace portion and the subsurface portion.The salt of <strong>[13614-98-7]minocycline</strong> may be a hydrochloride, wherein sparging decreases the amount of hydrogen chloride in the reactor vessel. Preferably, the amount of hydrogen chloride is decreased by up to 95%.A study was conducted on the effect of inert gas (such as nitrogen) sparging and use of vacuum on gaseous hydrogen chloride removal prior to addition of nitric acid. Reaction parameters set for each experiment were as follows: 40 g <strong>[13614-98-7]minocycline</strong>, multi-neck 250 ml round-bottom flask (diameter 8 cm), impeller length 4 cm, mixing speed 100 rpm (i.e. under poor mixing conditions). The following experiments were performed: 1. Nitrogen sparging in the headspace (50 ml/min); 2. Nitrogen sparging sub-surface (50 ml/min); 3. Vacuum (300 torr); 4. No sparging. Samples of dissolved <strong>[13614-98-7]minocycline</strong> in sulfuric acid at selected times were analyzed for chloride content as shown in Table 4. The chloride content of <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> was 6.8%. TABLE 4 CHLORIDE CONTENT OF MINOCYCLINE IN SULFURIC ACID AT SELECTED TIMES Time (mins) after Time (mins) after Chloride complete Chloride complete dissolution content dissolution of content of <strong>[13614-98-7]minocycline</strong> (ppm)* <strong>[13614-98-7]minocycline</strong> (ppm) Subsurface nitrogen Headspace nitrogen sparging sparging 0 1527 0 1725 30 1515 30 1673 60 1549 60 1941 90 1497 90 1674 180 1282 180 1750 Vacuum No sparging 0 1852 0 2253 30-No. 30 2269 60 1640 60 2224 90 1607 90 2349 *chloride content determined by IC.No.not determined.The experimental data suggests that nitrogen sparging has the ability to remove HCl from the system. Subsurface sparging showed a slightly better ability to remove HCl. Using a vacuum pull (300 torr) was comparable to nitrogen sparging in the headspace.An additional experiment on 40 g scale with the identical setup describe above (250 ml round-bottom flask, 4 cm impeller length) but with the mixing speed increased to 500 rpm, the residual HCl was reduced to 623 ppm after 1 hour under vacuum (300 torr). This experiment undoubtedly shows mixing speed affects the removal of HCl as shown in Table 5. Following these observations, an experiment was performed on a 250 g scale in a 2-L round-bottom flask with impeller length 11 cm and vacuum applied at 300 torr. The mixing speed was 500 rpm. After 2 hr under vacuum, a sample of the <strong>[13614-98-7]minocycline</strong> in sulfuric acid showed the chloride content to be 138 ppm. Increasing the stirring rate will increase efficiency of HCl removal. In the experiments on 40 g scale, increasing the stirring rate 5-fold resulted in an approximately 2.5-fold decrease in HCl content. Vacuum range is 20 to 300 torr and speed is 100 to 500 rpm. TABLE 5 EFFECT OF STIRRING AND VACUUM PRESSURE ON CHLORIDE CONTENT Chloride Hold time Stir rate Pressure content (min) (rpm) (torr) (ppm)* 0 100 300 1548 60 500 300 623 60 500 50 146 60 500 Full vac (<30) 69 *reporting limit: 50 ppm Effect of Stirring and Vacuum on Hydrogen Chloride Removal Further studies on the effect of stirring and effect on vacuum pressure on hydrogen chloride removal were conducted. The following data was collected on 40 g <strong>[13614-98-7]minocycline</strong> dissolved in 120 ml sulfuric acid in a 250-ml multi-neck round-bottom flask (diameter 8 cm), impeller length 4 cm as shown in Table 5 above, summarizes the chloride content of the solution on stirring rate and vacuum pressure.Hydrogen chloride removal was dependent on the mixing rate and vacuum pressure. The chloride content was reduced by 60% (1548 ppm to 623 ppm) when the stir rate was increased from 100 rpm to 500 rpm as shown in Table 5_above while maintaining the vacuum pressure at 300 torr for 1 hr. When the vacuum pressure was decreased to 50 torr while maintaining the stir rate at 500 rpm, a further 77% decrease in chloride content was obtained. A further drop to full vacuum reduced the chloride content of the solution to 69 ppm. To efficiently remove residual hydrogen chloride upon dissolution of <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> in sulfuric acid, the stirring rate should be relatively fast (500 rpm or above) as well as a vacuum pressure (300 torr or less) should be applied for a minimum of 1 hr. Full vacuum for the specific equipment used is an embodiment of this application. Vacuum range is 20 to 300 torr and spee...
  • 29
  • C34H49N3O9Si [ No CAS ]
  • [ 13614-98-7 ]
  • 30
  • [ 108-24-7 ]
  • [ 13614-98-7 ]
  • 3,10-diacetoxy-2-acetylcarbamoyl-4,7-bis-dimethylamino-12-hydroxy-11-oxo-5,5a,6,11-tetrahydronaphthacen-1-yl acetate [ No CAS ]
  • 3,10,12-triacetoxy-2-acetylcarbamoyl-4,7-bis-dimethylamino-11-oxo-5,5a,6,11-tetrahydronaphthacen-1-yl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
at 4 - 75℃; for 3h; Minocycline hydrochloride (0.60 g; 1.215 mmol) was dissolved under ice-cooling (4 C.) in 12 ml pyridine (11.73 g; 148.37 mmol) and then 12 ml acetanhydrid (12.98 g, 127.18 mmol) was added under stirring. Afterwards, the mixture was stirred at 4 C. during 30 minutes, at room temperature during 2 hours and at 75 C. during 30 minutes. The reaction product was cleaned by means of vacuum liquid chromatography (VLC). For this purpose, silica gel 60 (75 g) was condensed in a glass filter funnel under vacuum extraction and preconditioned with gasoline-kerosene (boiling range: 40-60 C.). The reaction mixture was loaded on the so prepared chromatography column and eluded with a gasoline-kerosene/ethyl acetate gradient (4/1, vol/vol to 100% EtOAc). Fractions that contained the reaction product were combined. After distilling off the solvent in the rotation evaporator a residual (518.5 mg) was obtained that was recrystallized from an ethyl acetate/gasoline-kerosene mixture and finally delivered the almost pure pentaacetyl cyclin as a light-yellow solid. The crude yield was 237.5 mg. A further VCL was performed for the final cleaning of the product. The pure yield was 181.9 mg (23% of theory). The analytic test of the individual fractions was made by means of thin film chromatography (DC with fluorescence indicator, polygram SIL G/UV254, company Macherey & Nagel) with silica gel 60 as the stationary phase and gasoline-kerosene/ethyl acetate (1/3, vol/vol) as the mobile phase. For cell culture experiments or for tests of the antibiotic effect strain solutions of the substance were produced in DMSO, sterilely filtered by means of nalgene nylon filters (pore size of 0.22 mum) and stored at -20 C. until their use.Analytical Data Pentaacetyl Cyclin (A-Ring Aromatized Pentaacetyl Minocycline):Rf (DC)=0.50UV-VIS (lambdamax in MeOH): 330 nm (log epsilon 4.27)LC/MS (positive ion mode): 723 [M+C3H6O2]+, 688 [M+K]+, 672 [M+Na]+, 650 [M+H]+, 608 [650-acetyl+H]+, 590 [608-H2O], 565 [608-acetyl]+, 548 [590-Acetyl+H]+, 506 [548-Acetyl+]+ HR-ESI-MS (negative ion mode): (M-H-) found 648.2198825, C33H34O11N3, dev. 2.5 ppmHR-ESI-MS: (M-Acetyl) found 606.2093178 (M-acetyl), C31H32O10N3, dev. 1.2 ppmHR-ESI-MS (positive ion mode): (M+Na+) found 672,21638, C33H35O11N3Na, dev. 2.4 ppm1H-NMR (DMSO-d6): delta (ppm) 2.16 (s, CH3); 2.23 (s, CH3); 2.27 (s, CH3); 2.28 (s, 2 CH3); 2.56 (m, CH); 2.66 (s, N(CH3)2); 2.73 (s, N(CH3)2); 2.76 (m, CH2, superimposed by N(CH3)2 signal); 3.48 (m, CH2); 7.00 (d, J=8.6 Hz, aromat. CH); 7.29 (d, J=8.2 Hz, aromat. CH); 11.08 (br s, NH)13C-NMR (DMSO-d6): signals, selection delta (ppm) 13.9; 20.2; 20.6; 24.6; 31.7; 42.4; 43.9; 59.5; 122.0; 124.5; 139.9; 148.5; 161.7; 167.2; 167.8; 168.1; 168.9; 169.8; Tetraacetyl cycline was chromatographically isolated as a by-product from the reaction mixture described in the embodiment and afterwards purely obtained from the corresponding fraction after distilling off the solvent and recrystallizing from a gasoline-kerosene/ethyl acetate mixture. Due to the bathochrome shift of the UV bands compared to the one of pentaacetyl cyclin of Formula II, the enol than, according to Formula IV, is the most probable one (FIG. 2). The other (not enolic) OH- or NH2-groups in the <strong>[13614-98-7]minocycline</strong> show a higher basicity and therefore they are preferably acetylated. The 1H-NMR spectrum (FIG. 3) supports the structure proof.Analytical Data Tetraacetyl Cyclin (A-Ring Aromatized Tetraacetyl Minocycline):Rf (DC)=0.57UV-VIS (lambdamax): 252.381 (log epsilon 4.27)LC/MS (positive ion mode): 681 [M+C3H6O2]+, 646 [M+K]+, 630 [M+Na]+, 608 [M+H]+, 566 [608-acetyl+H]+, 548 [566-H2O]+, 524 [566-acetyl+H]+, 506 [524-H2O]+ 1H-NMR (DMSO-d6): delta (ppm) 2.16 (s, CH3); 2.22 (s, CH3); 2.27 (s, CH3); 2.29 (s, CH3); 2.49 (dt, J=13.7 Hz, CH2); 2.63 (m, J=4.5; 13.6 Hz; CH); 2.66 (s, N(CH3)2); 2.72 (s, N(CH3)2); 3.50 (dt, J=4.5; 14.9 Hz; CH); 7.04 (d, J=8.6 Hz; aromat. CH); 7.37 (d, J=8.6 Hz; aromat. CH); 11.10 (s, NH)
  • 31
  • [ 13614-98-7 ]
  • [ 149934-17-8 ]
YieldReaction ConditionsOperation in experiment
NitrationMinocycline, an example of a compound of formula 2, was prepared according to the method described in U.S. Pat. No. 3,226,436. Minocycline chloride was then nitrated according to the following procedure:To 15 g of 98% sulfuric acid was added 5.3 g of <strong>[13614-98-7]minocycline</strong> chloride in several portions at 10 - 30 0C. The suspension was stirred under N2 for 4 hrs at 20 0C forming a homogeneous solution. To this solution was added 2.2 ml_ of isopropyl nitrate slowly to maintain the reaction temperature below 30 0C. After addition the reaction was aged for another 2 hrs. The reaction mixture was slowly added to IPA/Hep solution (125 mL/25 ml_) below 10 0C and then the solution was agitated for another 1 hr at this temperature. The formed solid was filtered and washed with pre-cooled 30 ml_ of IPA. The solid was dried at vacuum oven at 40 0C for 20 hrs. A yellow solid (7.3 g, 91.3% wt purity, 92.6% yield) was obtained for next reaction without further purification.Reduction after isolation of an intermediate formed from the nitration reactionTo a pressured glass bottle was added 50 ml_ of methanol and 10 ml_ of sulfuric acid. Previously prepared 9-nitro<strong>[13614-98-7]minocycline</strong> sulfate 5 g was added at 5 0C in one potion. To the solution was added 0.4g of 10% Pd/C and then the suspension was purged with N2 for three times and with H2 once. The suspension was maintained under H2 at a pressure of 45 PSI for 3 hr at 20 0C in a Parr Shaker. After removing the catalyst by a simple filtration, the reaction solution was added to IPA/Hep solution (100 mL/30 m L) at 5 - 10 0C. The solid was filtered and washed with pre-cooled 20 m L of IPA. The solid was dried at 40 0C for 20 hrs in a vacuum oven affording a yellow solid (4.3g, 74% wt pure) with a yield of 76%.Reduction without isolation of any intermediate formed from the nitration reactionTo 15 g of 98% sulfuric acid was added 5.3 g of <strong>[13614-98-7]minocycline</strong> chloride in several portions at 10 - 30 0C. The suspension was stirred under N2 for 4 hrs at 20 0C forming a homogeneous solution. To this solution was added 2.2 ml_ of isopropyl nitrate slowly to maintain the reaction temperature below 30 0C. After addition the reaction was aged for another 2 hrs. The reaction mixture was diluted with 50 ml. of methanol at 5- 10 oC and then added 1 g of 10% Pd/C. The suspension was purged with N2 for three times, with H2 once and then maintained under H2 at a pressure of 45 PSI for 3 hrs in a Parr shaker. After removing the catalyst by a simple filtration, the reaction solution was added to IPA/Hep solution (250 mL/50 mL) at 5 - 10 0C. The solid was filtered and washed with pre-cooled 40 mL of IPA. The solid was dried at 40 0C for 20 hrs in a vacuum oven affording a yellow solid (7.4g, 72% wt pure) with a yield of 87%.AcylationThe acylation of the compound of formula 4 may be performed as disclosed above. The Acylation is also disclosed in U.S. Patent Publication No. 2007-0049560 A1 paragraphs [0143] - [0213], incorporated by reference herein.PurificationThe Purification of the compound of formula 1 may be performed as disclosed above. Purification is also disclosued in U.S. Patent Publication No. 2007-0049560 A1 paragraphs [0214] - [0283], incorporated by reference herein.
  • 32
  • [ 13614-98-7 ]
  • [ 10118-90-8 ]
YieldReaction ConditionsOperation in experiment
55.4% With acetic acid; In methanol; at 42℃; for 3h; Was added 500ml of methanol, 40ml of acetic acid in 1L reaction flask, with stirring hydrochloric acid was added 40g minocycline. Warmed to 42 , the reaction incubated 3h, heating was stopped, cooled 0 ~ 5 , control the temperature dropping ammonia, adjusting the pH to 7.8-8.0 to precipitate a pale yellow solid temperature 0-5 stirred 2h, pH retest value unchanged, filtered, and the filter cake was washed with methanol, and dried under reduced pressure at room temperature after 4h, to give tigecycline impurities E20.5g, purity 98.6%, yield 55.4%.
With sodium hydrogencarbonate; In water;pH 6.5 - 7.0; Synthesis of 4-trimethylammonium tetracyclines 2.; The HCl salt of minocycline or sancycline (0.406 mol) was suspended in 3 L water. The pH was adjusted to 6.5-7.0 using NaHCO3 (68 g, 0.812 mol for minocycline and 34 g, 0.406 mol for sancycline) in 3 portions. The solution was then extracted with 2 x 1.5 L CH2Cl2. The solution was concentrated to dryness to give the tetracycline as the free base 1.
  • 33
  • minocycline hydrochloride [ No CAS ]
  • [ 10118-90-8 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; In dichloromethane; water;pH 8 - 9; Minocycline hydrochloride was added to a separatory funnel containing H20 and dichloromethane. To this was added saturated sodium bicarbonate until the pH was 8-9 by pH paper and the funnel was vigorously shaken. The organic layer was then separated and the aqueous layer was washed 4 times with dichloromethane. The organic layer was dried with magnesium sulfate, filtered, and concentrated to give the freebase of minocycline as a bright orange solid
With sodium hydrogencarbonate; In water;pH 6.5 - 7; Minocycline/HCl salt (200 g, 0.406 mol) was suspended in 3 L water and an amount of NaHCO3 (34 g, 0.406 mol) was added in 3 portions and the pH was adjusted to 6.5-7.0. The solution was then extracted with 2×1.5 L CH2Cl2. The solution was concentrated to dryness to give minocycline as the freebase, then redissolved in THF (1.6 L) and was charged in a 3 L 3-necked flask equipped with an over-head stirrer and a temperature probe while under argon. An amount of methyl iodide (289 g, 2.03 mol) was added and the solution was heated at 40-45 C. for approximately 16 hours, at which point it was verified by HPLC that no minocycline was left in solution. The solution was then poured into 6 L of heptane while on ice bath and stirred for at least 20 minutes at <5 C. The precipitate was filtered and washed with hexane (400 mL). The solid was dried under reduced pressure to a constant weight. An amount of 186 g methylammonium salt of minocycline was isolated.
  • 34
  • [ 13614-98-7 ]
  • [ 1420294-39-8 ]
  • 35
  • [ 13614-98-7 ]
  • [ 1420294-42-3 ]
  • 36
  • [ 13614-98-7 ]
  • [ 1420294-43-4 ]
  • 37
  • [ 13614-98-7 ]
  • [ 1420294-44-5 ]
  • 38
  • [ 13614-98-7 ]
  • [ 1420294-45-6 ]
  • 39
  • [ 13614-98-7 ]
  • [ 1420294-46-7 ]
  • 40
  • [ 13614-98-7 ]
  • [ 1420294-47-8 ]
  • 41
  • [ 13614-98-7 ]
  • [ 1420294-51-4 ]
  • 42
  • [ 13614-98-7 ]
  • [ 1420294-52-5 ]
  • 43
  • [ 13614-98-7 ]
  • [ 1420294-56-9 ]
  • 44
  • [ 13614-98-7 ]
  • [ 1420294-57-0 ]
  • 45
  • [ 13614-98-7 ]
  • (4S,4aS,5aR,12aS)-9-((6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide hydrochloride [ No CAS ]
  • 46
  • [ 13614-98-7 ]
  • [ 1420294-38-7 ]
  • 47
  • [ 13614-98-7 ]
  • [ 1420294-62-7 ]
  • 48
  • [ 13614-98-7 ]
  • [ 1420294-59-2 ]
  • 49
  • [ 13614-98-7 ]
  • [ 1420294-60-5 ]
  • 50
  • [ 13614-98-7 ]
  • [ 1420294-61-6 ]
  • 51
  • [ 13614-98-7 ]
  • (4S,4aS,5aR,12aS)-9-iodo-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carbox amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
22.8 g With N-iodo-succinimide; methanesulfonic acid; at 20℃; for 3h; To methanesulfonic acid (200mL) was added <strong>[13614-98-7]<strong>[13614-98-7]minocycline</strong> hydrochloride</strong> (28g) slowly portionwise. After complete dissolution of the compound, NIS(38g, 168.9mmol) was added portionwise at room temperature within 3 hours. Then the reaction mixture was poured into 20mL of ice-water in which 17.9g of sodium thiosulfate had been dissolved, and followed by vigorous stirring for 30 minutes. The obtained mixture was washed with ethyl acetate, and the aqueous phase was poured into a mixture of sodium bicarbonate (260g) and n-butanol (300mL), stirred, kept stand and separated. The aqueous phase was extracted with n-butanol again. The organic phases were combined and washed with water and a saturated aqueous solution of sodium chloride once respectively, and then rotary evaporated to remove solvents, dried in vacuo to give 22.8g of Compound B as a yellow solid.
  • 52
  • [ 13614-98-7 ]
  • [ 488818-70-8 ]
  • 53
  • [ 13614-98-7 ]
  • [ 1420294-36-5 ]
  • 54
  • [ 13614-98-7 ]
  • [ 1420294-37-6 ]
  • 55
  • [ 100-39-0 ]
  • [ 13614-98-7 ]
  • 3,10-dibenzyloxyminocycline hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Synthesis of 3,10-Dibenzyloxy<strong>[13614-98-7]minocycline</strong> (0158) (0159) 60% NaH in a mineral oil dispersion (152 mg, 3.8 mmol) was added in small portions to a stirred solution of <strong>[13614-98-7]minocycline</strong> HCl salt (0.5 g, 0.95 mmol) in DMF (5 mL) at room temperature. The resulting suspension was stirred at room temperature for 5 minutes. Benzyl bromide (0.34 mL, 2.84 mmol) was added and heated at 60 C. for 1 hour. The reaction mixture was then cooled to room temperature and quenched with ether (100 mL). The ether was then decanted and the remaining solid was dissolved in MeOH/water and the product was purified by preparative HPLC. The product was then converted to HCl salt to give 3,10-dibenzyloxy<strong>[13614-98-7]minocycline</strong> as an olive green solid.
  • 56
  • [ 542-69-8 ]
  • [ 13614-98-7 ]
  • 10-butyloxyminocycline hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Synthesis of 10-Butyloxy<strong>[13614-98-7]minocycline</strong> (0156) (0157) 60% NaH in a mineral oil dispersion (152 mg, 3.8 mmol) was added in small portions to a stirred solution of <strong>[13614-98-7]minocycline</strong> HCl salt (0.5 g, 0.95 mmol) in DMF (5 mL) at room temperature. The resulting suspension was stirred at room temperature for 5 minutes. Iodobutane (0.325 mL, 2.85 mmol) was added and heated at 60 C. for 1 hour. The reaction mixture was cooled to room temperature and quenched with ether (100 mL). The ether was subsequently decanted and the remaining solid was dissolved in MeOH/water. The product was purified by preparative HPLC and converted to the HCl salt to give 10-butyloxy<strong>[13614-98-7]minocycline</strong> as an olive green solid.
  • 57
  • [ 13614-98-7 ]
  • Omadacycline [ No CAS ]
  • 58
  • [ 13614-98-7 ]
  • 9-methyl aminominocycline trihydrochloride [ No CAS ]
  • 59
  • [ 118-29-6 ]
  • [ 13614-98-7 ]
  • C41H37N5O11 [ No CAS ]
  • C50H42N6O13 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With methanesulfonic acid; Methanesulfonic anhydride; at 20 - 35℃; Minocycline hydrochloride was dissolved in methylsulfonic acid or hydrofluoric acid with methyl sulfonic anhydride. N-hydroxymethyl phthalimide was added to the reaction mixture. The mixture was stirred at 20-35 C until the reaction was complete. The acid solution was added to an ice/water mixture and the triflic salt was readily precipitated, filtered and collected. The salt was re-dissolved in acetone and brought to a neutral pH with base. The product was precipitated by the addition of water. The product was isolated as a mixture of the bis and tris alkylated product. The isolated material of this reaction was enriched in the desired bis ratio (90%).
  • 60
  • [ 118-29-6 ]
  • [ 13614-98-7 ]
  • [ 835877-68-4 ]
YieldReaction ConditionsOperation in experiment
Minocycline hydrochloride was dissolved in methylsulfonic acid or hydrofluoric acid with methyl sulfonic anhydride. N-hydroxymethyl phthalimide was added to the reaction mixture. The mixture was stirred at 20-35 C until the reaction was complete. The acid solution was added to an ice/water mixture and the triflic salt was readily precipitated, filtered and collected. The salt was re-dissolved in acetone and brought to a neutral pH with base. The product was precipitated by the addition of water. The product was isolated as a mixture of the bis and tris alkylated product. The isolated material of this reaction was enriched in the desired bis ratio (90%). The solid was suspended in the EtOH. Aminolysis was carried out by using methylamine. A phthalamide by-product precipitated as the reaction progressed and was removed by filtration. The light yellow solid product was precipitated out by the addition of about 1.5 volumes of t-butylmethylether to the reaction mixture, and collected through a simple filtration that left many small impurities and methylamine reagent in the solution. Further purification of the compound was performed through re-slurrying with methanol.
  • 61
  • [ 137-08-6 ]
  • [ 13614-98-7 ]
  • minocyclin-mono-pantothenate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethanol; water; Example 28 Preparation of Minocyclin-Mono-Pantothenate (0124) 3.3 g Minocyclin hydrochloride (Sigma Aldrich) in 50 mL of a 50% ethanolic solution in deionized water and 1.7 g calcium dipantothenate dissolved in 35 mL of deionized water were added to each other and combined with additional 35 mL of water. The solution was filtered and evaporated in a rotary evaporator at 50 C. to dryness and the precipitated solid was taken up in methanol. The methanolic suspension was then centrifuged and the sediment was dried overnight.
  • 62
  • [ 542-69-8 ]
  • [ 13614-98-7 ]
  • 10-butoxy-4,7-bis-dimethylamino-3,12,12a-trihydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydronaphthacene-2-carboxylic acid amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% 129 NaH in a 130 mineral oil dispersion (152 mg, 3.8 mmol) was added in small portions to a stirred solution of 136 <strong>[13614-98-7]minocycline</strong> HCl salt (0.5 g, 0.95 mmol) in 24 DMF (5 mL) at room temperature. The resulting suspension was stirred at room temperature for 5 minutes. 137 Iodobutane (0.325 mL, 2.85 mmol) was added and heated at 60 C. for 1 hour. The reaction mixture was cooled to room temperature and quenched with ether (100 mL). The ether was subsequently decanted and the remaining solid was dissolved in 8 MeOH/22 water. The product was purified by preparative HPLC and converted to the HCl salt to give 138 10-butyloxy<strong>[13614-98-7]minocycline</strong> as an olive green solid.
  • 63
  • [ 10118-90-8 ]
  • [ 13614-98-7 ]
YieldReaction ConditionsOperation in experiment
92.7% With hydrogenchloride In ethanol at 0 - 5℃; for 1h; 21-22 General procedure: 10g of Intermediate IV was dissolved in 30ml methanol, cooled to 0-5°C, concentrated hydrochloric acid was added dropwise to adjust Ph to 1-2, after stirring for 1h, a white suspension was obtained, filtered, the filter cake was washed with a small amount of methanol, and dried to obtain 9g of white solid powder (minocycline hydrochloride), the molar yield is 83.4%, and the HPLC purity is 98.5%.
  • 64
  • [ 13614-98-7 ]
  • [ 1075240-43-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: trifluorormethanesulfonic acid / 30 min / 20 - 30 °C 2.1: methanol; methylamine / 1.5 h / 20 - 30 °C 3.1: 10% Pd/C; hydrogen; 2,6-di-tert-butyl-4-methyl-phenol; triethylamine / methanol / 18 - 23 °C / 2585.81 - 3620.13 Torr 3.2: 20 - 30 °C
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