WO2011045815A2 - Process for the preparation of lamivudine and novel salts in the manufacture thereof - Google Patents
Process for the preparation of lamivudine and novel salts in the manufacture thereof Download PDFInfo
- Publication number
- WO2011045815A2 WO2011045815A2 PCT/IN2010/000679 IN2010000679W WO2011045815A2 WO 2011045815 A2 WO2011045815 A2 WO 2011045815A2 IN 2010000679 W IN2010000679 W IN 2010000679W WO 2011045815 A2 WO2011045815 A2 WO 2011045815A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lamivudine
- solvent
- preparation
- acid
- formula
- Prior art date
Links
- 0 CC[C@](CC[C@@](C)C1)[C@@]1OC([C@@]1SC[C@@](N2C=C3)O1)=*=C2N=C3N Chemical compound CC[C@](CC[C@@](C)C1)[C@@]1OC([C@@]1SC[C@@](N2C=C3)O1)=*=C2N=C3N 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N NC(C=CN1[C@H]2O[C@@H](CO)SC2)=NC1=O Chemical compound NC(C=CN1[C@H]2O[C@@H](CO)SC2)=NC1=O JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to novel salts of Lamivudine and method for the preparation thereof.
- the present invention also relates to processes for the preparation of crystalline Lamivudine Form-I and Form-II from novel salts of Lamivudine. BACKGROUND OF THE INVENTION
- US 5905082 patent provides a process for the preparation of Lamivudine by enzymatic separation. This patent also discloses the existence of two polymorphic forms of Lamivudine viz., needle-shaped crystals (Form-I) and bipyramidal crystals (Form-II). It also discloses the processes for the preparation of Form-I and Form-II.
- the present invention provides novel acid addition salts of Lamivudine and process for the preparation of Lamivudine from these salts.
- the recovery of acid is quantitative and quality of Lamivudine is better than salicylate process.
- the present process is cost effective and can be commercialized in large scale.
- the present invention provides novel acid addition salt of (+)-(2R, cis)-4- amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one, represented by
- the present invention provides novel (+)-(2i?, cis)-4-amino-l-(2- hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one, 3-hydroxy-2-naphthoic acid salt represented by Formula IIIA.
- the present invention provides a process for the preparation of Formula III, comprising the steps of: a) reducing the compound of Formula II with metallic borohydride in solvent, b) adding 3-hydroxy-2-naphthoic acid or L-pyroglutamic acid or 2- methoxybenzoic acid, and c) isolating acid addition salt of Lamivudine of Formula III.
- the present invention provides a process for the preparation of Lamivudine Form-I, comprising the steps of: a) dissolving Lamivudine in a mixture of solvents, b) optionally removing the solvent, c) cooling the resultant solution, and d) isolating the Lamivudine Form-I.
- the present invention provides a process for the preparation of Lamivudine Form-II, comprising the steps of: a) suspending Lamivudine in solvent, b) removing some part of the solvent, c) cooling the resultant solution, and d) isolating the Lamivudine Form-II.
- the entire process for the preparation of Lamivudine according to the present invention is as depicted in Scheme 1 below.
- FIG. 1 is a representative X-ray diffraction pattern of (+)-(2R, cw)-4-amino-l-(2- hydroxymethyl-1, 3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one 3-hydroxy-2-naphthoic acid salt (Formula IIIA).
- the present invention provides a process for the preparation of acid addition salt of Lamivudine of Formula III,
- the acid is selected from 3-hydroxy-2-naphthoic acid, methoxybenzoic acid or L- pyroglutamic acid.
- Another solvent is selected from ethanol, methanol, n-propanol, 2- propanol, acetone or methyl isobutyl ketone.
- the present invention provides a process for the preparation of Lamivudine comprising the steps of:
- compound of Formula III is suspended in solvent, treated with a base, heated the reaction mixture to get a clear solution and cooled to room temperature to crystallize the Lamivudine.
- the present invention relates to 4-amino-l-(2if-hydroxymethyl-[l ,3]- oxothiolane-55'-yl)-lH-pyrimidin-2-one L-pyroglutamic acid salt, represented by Formula IIIB.
- the present invention provides a process for the preparation of Lamivudine Form-I comprising the steps of:
- Lamivudine is suspended in solvent and heated to reflux to get a clear solution.
- the solvent is removed to about 30-95%, preferably 50-90% using conventional technique.
- the resultant mass is cooled to 5-20°C and isolated the Lamivudine Form-II by filtration.
- the solvent for the suspension of Lamivudine is selected from methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, 2-butanol, water or mixture thereof.
- the conventional technique for solvent removal is distillation or evaporation.
- the X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker D8 Discover powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and LynxEye detector.
- the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
- EXAMPLE-1 Preparation of 4-amino-l-(2R-hydroxymethyl-[l, 3]-oxothiolane-5S-yl)-lH- pyrimidin-2-one mononaphthylate (Lamivudine 3-hydroxy-2-naphthoic acid salt)
- Ethanol 600 mL was added to a solution of dipotassium hydrogen phosphate (137 g in 220 mL of water) and the mass was cooled to 18°C. (17?, 2'S, 5'i?)-Menthyl- SS'-cytosin-T'-yl-l ⁇ - oxathiolane-2i?-carboxylate (Formula II, 100 g) was added at 15-20°C and maintained for 1 h. A solution of sodium borohydride (48 g in 95 mL of 0.12N sodium hydroxide) was added drop wise by keeping temperature at 18-20°C and maintained for 4 h. After completion of the reaction, the layers were separated.
- the organic layerf pH was adjusted to 6.0-6.5 with 6N HC1 (-13 mL) and re-adjusted to pH 8.0 to 8.5 with 2N sodium hydroxide.
- Ethanol (-790 mL) was distilled out from the reaction mass under reduced pressure.
- the resultant mass was cooled to 30-35 °C, diluted with water (200 mL) under stirring and maintained for 15 min.
- the obtained aqueous layer was washed with toluene (100 mL) and charcoalised.
- 3-Hydroxy 2-naphthoicacid (48.92 g) and acetone (300 mL) were added to the aqueous layer and then heated to 60-65 °C to obtain a clear solution.
- EXAMPLE-2 Preparation of 4-amino-l-(2R-hydroxymethyl-[l, 3]-oxothiolane-5S-yl)- lH-pyrimidin-2-one mononaphthylate (Lamivudine 3-hydroxy-2-naphthoicacid salt)
- Ethanol 600 mL was added to a solution of dipotassium hydrogen phosphate (83.3 g in 220 mL of water) and the mass was cooled to 18°C.
- VR, 2'S, 5'i?)-Menthyl-55'-cytosin-l "-yl-l, 3-oxathiolane-2i?-carboxylate (Formula II, 100 g) was added at 12-18°C and maintained for 1 h.
- a solution of sodium borohydride (20 g in 95 mL of 0.5 g of sodium hydroxide) was added drop wise by keeping temperature at 12-18 °C and maintained for 4 h. After completion of the reaction, the layers were separated.
- Reaction mass diluted with purified water (100 mL), heated to 82- 88°C and cooled to 10-15°C.
- the separated solid was filtered and washed with chilled purified water (50 mL).
- the wet cake was added into purified water (300 mL) and stirred for 60 min. at 30-35°C. Further, cooled to 10-15°C and allowed to stir for 2 h.
- the separated solid was filtered and washed with chilled purified water (50 mL). The material was dried at 71-75°C to yield Lamivudine 3-hydroxy-2-naphthoicacid salt in 90g. Diastereomer impurity: ⁇ 0.5%.
- EXAMPLE-4 Preparation of preparation of 4-amino-l-(2R-hydroxymethyl-[l, 3]- oxothiolane-5S-yl) lH-pyrimidin-2-one 2-methoxybezoicacid salt (Lamivudine 2- methoxybezoicacid salt)
- 2-Methoxy benzoic acid 39.62 g was added to the aqueous layer (700 mL) from Example- 1 (after toluene washings) and heated to 60-65°C to obtain a clear solution.
- the reaction mass was stirred for 30 min and diluted with water (100 mL) at 60-65°C.
- the reaction mass was cooled to 0-5°C and allowed to stir for 2 h.
- the separated solid was filtered, washed with chilled methanol (50 mL) and dried under vacuum at 45-50°C to get Lamivudine 2-methoxy benzoic acid in 75 g.
- Lamivudine naphthylate (90 g) was suspended in a mixture of acetone (500 mL), methanol (50 mL) and triethylamine (48.4 g) at 25-30°C. The reaction was heated to 50-55°C and maintained for 2 h. The reaction was cooled to 21-25°C over a period of 3 h. to crystallize the material. The separated solid was filtered, washed with acetone (50 mL). The wet cake was added into acetone (300 mL), heated to 50-55°C and maintained for 60 min. The reaction was cooled to 21-25°C over a period of 60 min. to crystallize the material. The separated solid was filtered, washed with acetone (50 mL). The material was dried at 40-45°C to yield Lamivudine in 45g. Diastereomer impurity: ⁇ 0.3%.
- Lamivudine methoxy benzoate (90 g) was suspended in aqueous acetone (300 mL) and triethylamine (47.66 g) was added at 25-30 °C. The reaction mass was heat to 40-45 °C and maintained for 30 min. The reaction mass was cooled to 25-30 °C over period of 60 min. to crystallize the material. The separated solid was filtered, washed with acetone (20 mL) and dried under vacuum at 45-50°C to afford Lamivudine in 50 g.
- EXAMPLE -9 Preparation of Lamivudine Form-I
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to novel salts of Lamivudine and method for the preparation thereof. The present invention also relates to processes for the preparation of crystalline Lamivudine Form-I and Form-II from novel salts of Lamivudine.
Description
"PROCESS FOR THE PREPARATION OF LAMIVUDINE AND NOVEL SALTS IN
THE MANUFACTURE THEREOF"
This patent application claims priority from Indian patent application 2492/CHE/2009 filed on Oct 14, 2009 FIELD OF THE INVENTION
The present invention relates to novel salts of Lamivudine and method for the preparation thereof. The present invention also relates to processes for the preparation of crystalline Lamivudine Form-I and Form-II from novel salts of Lamivudine. BACKGROUND OF THE INVENTION
Lamivudine of Formula I is an antiviral drug presently marketed by GlaxoSmithkline and is available as "EPIVIR", indicated for the treatment against retroviruses such as Human immuno deficiency virus (HIV), Hepatitis B virus (HBV) and Human T-Lymphotrophic virus (HTLV).
Formula I
US 5047407 patent describes the preparation of (+)-(2R, c 5,)-4-amino-l-(2-hydroxymethyl- 1 , 3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one (Lamivudine, 3TC), its antiviral activity and its use in pharmaceutical product. US 6051709 patent discloses the process for the preparation of pure Lamivudine, in which Lamivudine isolated from its salicylate salt during the diastereoselective process development.
US 5905082 patent provides a process for the preparation of Lamivudine by enzymatic separation. This patent also discloses the existence of two polymorphic forms of Lamivudine
viz., needle-shaped crystals (Form-I) and bipyramidal crystals (Form-II). It also discloses the processes for the preparation of Form-I and Form-II.
WO 2007119248 A 1 application provides novel monoclinic crystals of Lamivudine and its process for the preparation.
WO 2008114279A2 application discloses the Form-Ill, Form-IV, Form-V and amorphous Lamivudine. It also discloses the processes for the preparation of Form-I and Form-II.
WO2009037538A2 application discloses a process for the preparation of Lamivudine of Form-I by dissolving Lamivudine in aqueous ethanol at 45-55°C then removing ethanol under reduced pressure below 42°C to obtain product as a solid residue, followed by addition of ethyl acetate / methyl isobutyl ketone to get Lamivudine Form-I.
The present invention provides novel acid addition salts of Lamivudine and process for the preparation of Lamivudine from these salts. In this process the recovery of acid is quantitative and quality of Lamivudine is better than salicylate process. The present process is cost effective and can be commercialized in large scale.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides novel acid addition salt of (+)-(2R, cis)-4- amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one, represented by
Formula III.
acid addition salt
Formula III
Wherein acid is selected from 3-hydroxy-2-naphthoic acid, L-pyroglutamic acid or 2- methoxybenzoic acid
In one aspect, the present invention provides novel (+)-(2i?, cis)-4-amino-l-(2- hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one, 3-hydroxy-2-naphthoic acid salt represented by Formula IIIA.
Formula IIIA
In another aspect, the present invention provides a process for the preparation of Formula III, comprising the steps of: a) reducing the compound of Formula II with metallic borohydride in solvent, b) adding 3-hydroxy-2-naphthoic acid or L-pyroglutamic acid or 2- methoxybenzoic acid, and c) isolating acid addition salt of Lamivudine of Formula III.
In another aspect, the present invention provides a process for the preparation of Lamivudine, comprising the steps of: a) reacting the compound of Formula III with a base in solvent and b) isolating the Lamivudine.
In another aspect, the present invention provides a process for the preparation of Lamivudine Form-I, comprising the steps of: a) dissolving Lamivudine in a mixture of solvents, b) optionally removing the solvent, c) cooling the resultant solution, and d) isolating the Lamivudine Form-I.
In yet another aspect, the present invention provides a process for the preparation of Lamivudine Form-II, comprising the steps of: a) suspending Lamivudine in solvent, b) removing some part of the solvent, c) cooling the resultant solution, and d) isolating the Lamivudine Form-II.
The entire process for the preparation of Lamivudine according to the present invention is as depicted in Scheme 1 below.
Scheme 1
Formula II Formula III Lamivudine
Wherein acid is selected from (Formula I)
3-hydroxy-2-naphthoic acid, 10
L-pyroglutamic acid or
2-methoxybenzoic acid
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a representative X-ray diffraction pattern of (+)-(2R, cw)-4-amino-l-(2- hydroxymethyl-1, 3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one 3-hydroxy-2-naphthoic acid salt (Formula IIIA).
DETAILED DESCRIPTION OF THE INVENTION Definitions
The word "suspend" in the present invention may be partly soluble or insoluble. The word "treat" in the present invention may be contact or react.
The present invention relates to novel salts of Lamivudine and method for the preparation thereof. The present invention also relates to processes for the preparation of crystalline Lamivudine Form-I and Form-II from novel salts of Lamivudine.
In one embodiment, the present invention provides novel acid addition salt of (+)-(2R, cis)-4- amino- 1 -(2-hydroxymethyl- 1 ,3-oxathiolan-5-yl)-( 1 H)-pyrimidin-2-one, represented by Formula III.
acid addition salt
Formula III
Wherein acid is selected from 3-hydroxy-2-naphthoic acid, L-pyroglutamic acid or 2- methoxybenzoic acid.
In another embodiment, the present invention provides a process for the preparation of acid addition salt of Lamivudine of Formula III,
acid addition salt
Formula III
Wherein acid is selected from 3-hydroxy-2-naphthoic acid, L-pyroglutamic acid or 2- methoxybenzoic acid.
Comprising the steps of:
a) reducing the compound of Formula II with metallic borohydride in solvent,
Formula II
b) adding 3-hydroxy-2-naphthoic acid or L-pyroglutamic acid or 2-methoxybenzoic acid, and
c) isolating the acid addition salt of Lamivudine Formula III.
According to the present invention, compound of Formula II is suspended in solvent and reduced with metallic borohydride in presence of dipotassium hydrogen phosphate at 15-
20°C. The resulting solution is added with an organic acid followed by addition of another solvent, heated to get a clear solution, cooled solution to room temperature and the obtained acid addition salt of Lamivudine is isolated by filtration.
The solvent used to dissolve the compound of Formula II is selected from ethanol, methanol, 1-propanol, 2-propanol, N, N-dimethylformamide, tetrahydrofuran, water or mixture thereof.
The metallic borohydride is selected from sodium borohydride, potassium borohydride or lithium borohydride.
The acid is selected from 3-hydroxy-2-naphthoic acid, methoxybenzoic acid or L- pyroglutamic acid. Another solvent is selected from ethanol, methanol, n-propanol, 2- propanol, acetone or methyl isobutyl ketone.
In another embodiment, the present invention provides a process for the preparation of Lamivudine comprising the steps of:
a) reacting the compound of Formula III with a base in solvent and
b) isolating the Lamivudine.
According to the present invention, compound of Formula III is suspended in solvent, treated with a base, heated the reaction mixture to get a clear solution and cooled to room temperature to crystallize the Lamivudine.
The solvent for the suspension of the compound of Formula III is selected from acetone, methyl isobutyl ketone, methanol, ethanol, 2-propanol, tetrahydrofuran, dioxane, ethyl acetate, water or mixture thereof. The base is selected from ammonia, triethylamine or Hunig's base.
In another embodiment, the present invention relates to 4-amino-l-(2i?-hydroxymethyl-[l,3]- oxothiolane-55'-yl)-lH-pyrimidin-2-one 3-hydroxy-2-naphthoic acid salt, represented by Formula IIIA.
Formula IIIA
In another embodiment, the present invention relates to 4-amino-l-(2if-hydroxymethyl-[l ,3]- oxothiolane-55'-yl)-lH-pyrimidin-2-one L-pyroglutamic acid salt, represented by Formula IIIB.
Formula IIIB
In another embodiment, the present invention relates to 4-amino-l-(2i?-hydroxymethyl-[l, 3]-oxothiolane-5S-yl)-lH-pyrimidin-2-one 2-methoxybezoic acid salt, represented by Formula IIIC.
Formula IIIC
In another embodiment, the present invention provides a process for the preparation of Lamivudine Form-I comprising the steps of:
a) dissolving Lamivudine in a mixture of solvents,
b) optionally removing the solvent,
c) cooling the resultant solution, and
d) isolating the Lamivudine Form-I.
According to the present invention, Lamivudine is dissolved in a mixture of solvents such as aqueous alcohol, preferably aqueous isopropyl alcohol, aqueous methanol or aqueous ethanol. The solution is then heated to reflux, removed the solvent to about 30-80%, preferably 50-70% using conventional technique, cooled to ambient temperature and isolated the Lamivudine Form-I by filtration. The conventional technique for solvent removal is distillation or evaporation.
In another embodiment, the present invention provides a process for the preparation of Lamivudine Form-II comprising the steps of:
a) suspending Lamivudine in solvent,
b) removing the solvent,
c) cooling the resultant solution, and
d) isolating the Lamivudine Form-II.
According to the present invention, Lamivudine is suspended in solvent and heated to reflux to get a clear solution. The solvent is removed to about 30-95%, preferably 50-90% using conventional technique. The resultant mass is cooled to 5-20°C and isolated the Lamivudine Form-II by filtration.
The solvent for the suspension of Lamivudine is selected from methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, 2-butanol, water or mixture thereof. The conventional technique for solvent removal is distillation or evaporation.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.
EXPERIMENTAL SECTION
Powder X-ray Diffraction (PXRD)
The X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker D8 Discover powder diffractometer equipped with goniometer of Θ/Θ configuration and LynxEye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
EXAMPLE-1: Preparation of 4-amino-l-(2R-hydroxymethyl-[l, 3]-oxothiolane-5S-yl)-lH- pyrimidin-2-one mononaphthylate (Lamivudine 3-hydroxy-2-naphthoic acid salt)
Ethanol (600 mL) was added to a solution of dipotassium hydrogen phosphate (137 g in 220 mL of water) and the mass was cooled to 18°C. (17?, 2'S, 5'i?)-Menthyl- SS'-cytosin-T'-yl-l^- oxathiolane-2i?-carboxylate (Formula II, 100 g) was added at 15-20°C and maintained for 1 h. A solution of sodium borohydride (48 g in 95 mL of 0.12N sodium hydroxide) was added drop wise by keeping temperature at 18-20°C and maintained for 4 h. After completion of the reaction, the layers were separated. The organic layerf pH was adjusted to 6.0-6.5 with 6N HC1 (-13 mL) and re-adjusted to pH 8.0 to 8.5 with 2N sodium hydroxide. Ethanol (-790 mL) was distilled out from the reaction mass under reduced pressure. The resultant mass was cooled to 30-35 °C, diluted with water (200 mL) under stirring and maintained for 15 min. The obtained aqueous layer was washed with toluene (100 mL) and charcoalised. 3-Hydroxy 2-naphthoicacid (48.92 g) and acetone (300 mL) were added to the aqueous layer and then heated to 60-65 °C to obtain a clear solution. The reaction mass was cooled to 10-15°C and allowed to stir for 2 h. The separated solid was filtered and washed with water (50 mL) followed by pre-cooled acetone (10 mL). The material was dried under vacuum at 45-50°C to yield Lamivudine 3-hydroxy-2-naphthoic acid salt in 90 g. Characterization of the title compound was confirmed by 1H-NMR and 13C-NMR.
Ή-NMR (DMSO-<¾, 300 MHz, ppm)- δ 3.1 1-3.16 (dd, J=4.4 & 1 1.9 Hz, 1H, 6Ha),
3.43-3.48 (dd, J=5.4 & 12 Hz, 1H, 6Hb), 3.77 (d, J=4.5 Hz, 2H, 8), 5.21 (t, J=4.5 Hz, 1H, 7), 5.86 (d, J=7.5Hz, 1H, 3), 6.22 (t, J=5.0 Hz, 1H, 5), 7.23-7.26 (m, 1H, 14'), 7.30-7.35 (m, 1H, 14), 7.46-7.53 (m, 1H, 1 1), 7.74 (d, J=8.4 Hz, 1H, 13), 7.86-7.98 (m, 1H, 13'), 7.97 (d, J=7.8 Hz, 1H, 4), 8.48-8.51 (m, 1H, 16).
13C-NMR (DMSO- 6, 75 MHz, ppm)- δ 37.03(6C), 62.19 (8C), 93.96(3C), 86.65(7C), 87.43(5C), 110.07(1 1C), 118.37(9C), 123.38(14'C), 125.76(13C), 126.64(15C), 128.18(16C), 129.05(14C), 131.96(13'C), 136.88(12C), 142.92(4C), 150.93 (1C), 157.12(10C), 162.65(2C), 172.44(17C).
EXAMPLE-2: Preparation of 4-amino-l-(2R-hydroxymethyl-[l, 3]-oxothiolane-5S-yl)- lH-pyrimidin-2-one mononaphthylate (Lamivudine 3-hydroxy-2-naphthoicacid salt)
Ethanol (600 mL) was added to a solution of dipotassium hydrogen phosphate (83.3 g in 220 mL of water) and the mass was cooled to 18°C. (VR, 2'S, 5'i?)-Menthyl-55'-cytosin-l "-yl-l, 3-oxathiolane-2i?-carboxylate (Formula II, 100 g) was added at 12-18°C and maintained for 1 h. A solution of sodium borohydride (20 g in 95 mL of 0.5 g of sodium hydroxide) was added drop wise by keeping temperature at 12-18 °C and maintained for 4 h. After completion of the reaction, the layers were separated. The organic layer pH was adjusted to 6.0-6.5 with 6N HC1 (-13 mL) and re-adjusted to pH 8.0 to 8.5 with 2N sodium hydroxide. Ethanol (450 mL) was distilled out from the reaction mass under reduced pressure. Then resultant mass was cooled to 30-35 °C, diluted with water (200 mL) under stirring. The obtained aqueous layer was washed with toluene (100 mL) and charcoalised. 3-Hydroxy2- naphthoicacid (49.4 g) was added to aqueous layer, heated to 82-88 °C to obtain a clear solution and charcoalised. Reaction mass diluted with purified water (100 mL), heated to 82- 88°C and cooled to 10-15°C. The separated solid was filtered and washed with chilled purified water (50 mL). The wet cake was added into purified water (300 mL) and stirred for 60 min. at 30-35°C. Further, cooled to 10-15°C and allowed to stir for 2 h. The separated solid was filtered and washed with chilled purified water (50 mL). The material was dried at
71-75°C to yield Lamivudine 3-hydroxy-2-naphthoicacid salt in 90g. Diastereomer impurity: <0.5%.
EXAMPLE 3: Preparation of 4-amino-l-(2R-hydroxymethyl-[l, 3]-oxothiolane-5S-yl) lH-pyrimidin-2-one L-Pyroglutamate (Lamivudine L-pyroglutamate)
Methanol (90 mL) and L-pyroglutamic acid (34.9 g) was added to the aqueous layer of Ex-1 (after toluene washings), heated to 60-65 °C to obtain a clear solution and maintained for 30 min. The reaction mass was cooled to 10 -15°C and allowed to stir for 2 h. The separated solid was filtered, washed with methanol (10 mL) and dried under vacuum at 45-50°C to afford Lamivudine L-pyroglutamate in 90 g.
EXAMPLE-4: Preparation of preparation of 4-amino-l-(2R-hydroxymethyl-[l, 3]- oxothiolane-5S-yl) lH-pyrimidin-2-one 2-methoxybezoicacid salt (Lamivudine 2- methoxybezoicacid salt)
2-Methoxy benzoic acid (39.62 g) was added to the aqueous layer (700 mL) from Example- 1 (after toluene washings) and heated to 60-65°C to obtain a clear solution. The reaction mass was stirred for 30 min and diluted with water (100 mL) at 60-65°C. The reaction mass was cooled to 0-5°C and allowed to stir for 2 h. The separated solid was filtered, washed with chilled methanol (50 mL) and dried under vacuum at 45-50°C to get Lamivudine 2-methoxy benzoic acid in 75 g.
EXAMPLE-5: Preparation of 4-amino-l-(2R-hydroxymethyI-[l,3]-oxothiolane-5S-yl) lH-pyrimidin-2-one (Lamivudine) from Lamivudine 3-hydroxy-2-naphthoic acid salt.
Lamivudine naphthylate (90 g) was suspended in 2% aqueous acetone (400 mL) and triethylamine (43.59 g) was added at 25-30 °C. The reaction mass was heated to 40-45°C and maintained for 30 min. The reaction mass was cooled to 25-30 °C over period of 60 min. to
crystallize the material. The separated solid was filtered, washed with acetone (20 mL) and dried under vacuum at 45-50°C to obtained Lamivudine in 46 g.
EXAMPLE-6: Preparation of 4-amino-l-(2R-hydroxymethyI-[l,3]-oxothiolane-5S-yl) lH-pyrimidin-2-one (Lamivudine) from Lamivudine 3-hydroxy-2-naphthoicacid salt.
Lamivudine naphthylate (90 g) was suspended in a mixture of acetone (500 mL), methanol (50 mL) and triethylamine (48.4 g) at 25-30°C. The reaction was heated to 50-55°C and maintained for 2 h. The reaction was cooled to 21-25°C over a period of 3 h. to crystallize the material. The separated solid was filtered, washed with acetone (50 mL). The wet cake was added into acetone (300 mL), heated to 50-55°C and maintained for 60 min. The reaction was cooled to 21-25°C over a period of 60 min. to crystallize the material. The separated solid was filtered, washed with acetone (50 mL). The material was dried at 40-45°C to yield Lamivudine in 45g. Diastereomer impurity: <0.3%.
EXAMPLE-7: Preparation of 4-amino-l-(2R-hydroxymethyl-[l,3]-oxothiolane-5S-yl) lH-pyrimidin-2-one (Lamivudine) from Lamivudine L-pyroglutamate.
Lamivudine L-pyroglutamate (80 g) was suspended in aqueous acetone (300 mL) and triethylamine (44.64 g) was added at 25-30 °C. The reaction mass was heated to 40-45 °C maintained for 30 min. the reaction mass was cooled to 25-30 °C over a period of 60 min. to crystallize the material. The separated solid was filtered, washed with acetone (10 mL) and dried under vacuum at 45-50°C to yield Lamivudine in 48 g.
EXAMPLE-8: Preparation of 4-amino-l-(2R-hydroxymethyl-[l,3]-oxothiolane-5S-yI) lH-pyrimidin-2-one (Lamivudine) from Lamivudine methoxy benzoate
Lamivudine methoxy benzoate (90 g) was suspended in aqueous acetone (300 mL) and triethylamine (47.66 g) was added at 25-30 °C. The reaction mass was heat to 40-45 °C and
maintained for 30 min. The reaction mass was cooled to 25-30 °C over period of 60 min. to crystallize the material. The separated solid was filtered, washed with acetone (20 mL) and dried under vacuum at 45-50°C to afford Lamivudine in 50 g. EXAMPLE -9: Preparation of Lamivudine Form-I
Lamivudine (100 g) was dissolved in a mixture of isopropyl alcohol (900 mL) and purified water (100 mL) at reflux temperature. Activated carbon was added to the solution and stirred for 30 min. at reflux temperature. The carbon was removed by filtration through hyflo and washed with 10% aq. isopropyl alcohol (100 mL). The filtrate was distilled under reduced pressure (>200 mm Hg) at below 45°C to about 50%. The resultant mass was cooled to 25- 35°C and maintain for 4 h. The separated product was filtered and washed with isopropyl alcohol (100 mL) and dried under reduced pressure at 50-55°C to yield Lamivudine Form-I (78 g, HPLC purity -99.8 %).
EXAMPLE -10: Preparation of Lamivudine Form-I
Lamivudine (20 g) was dissolved in a mixture of isopropyl alcohol (120 mL) and purified water (10 mL) at reflux temperature. Activated carbon was added to the solution and stirred for 30 min. at reflux temperature. The carbon was removed by filtration through hyflo and washed with 7% aq. isopropyl alcohol (20 mL). The reaction mass was cooled to 25-35 °C and maintained for 4 h. The separated product was filtered and washed with isopropyl alcohol (20 mL) and dried under reduced pressure at 50-55°C to yield Lamivudine Form-I (15 g, HPLC purity -99.8 %).
EXAMPLE-11: Preparation of Lamivudine Form-II
Lamivudine (60 g) was added to 2-propanol (1800 mL) and heated to 60-65 °C to obtain a clear solution. The activated carbon (4 g) was added, stireed for 30 min and filtered. Around
50% of isopropanol (~900 mL) was distilled out from the reaction mass under vacuum at below 60°C. The reaction mass cooled to 25-30 °C over a period of 60 min to crystallize the material. Further, reaction mass cooled to 10-15°C and stirred for 2 h. The separated solid was filtered, washed with chilled 2-propanol (30 mL) and dried under vacuum at 45-50°C to get pure Lamivudine Form-II (50 g, HPLC purity 99.5%).
EXAMPLE -12: Preparation of Lamivudine Form-II
Lamivudine (45 g) was added to isopropylalchol (1350 mL) at 30-35°C and heated to 78- 82°C to obtain a clear solution. The activated carbon (4.5 g) was added, stirred for 30 min. and filtered. Around 70% of isopropylalchol (-1040 mL) was distilled out from the reaction mass under vacuum at below 80°C. The reaction mass cooled to 30-35°C over a period of 4 h. to crystallize the material and maintain for 6 h. Further, reaction mass cooled to 9-15°C over a period of 4 h. and maintain for 2 h. The separated solid was filtered, washed with chilled isopropylalchol (22.5 mL). The material was dried under vacuum at 45-50°C to get pure Lamivudine Form-II in 40.5 g. Diastereomer impurity: <0.1%
Claims
We Claim
1 A process for the preparation of acid addition salt of Lamivudine Formula III
acid addition salt
Formula III
wherein acid is selected from 3-hydroxy-2-naphthoic acid, L-pyroglutamic acid or 2- methoxybenzoic acid.
Comprising the steps of:
a) reducing the compound of Formula II with metallic borohydride in solvent,
Formula II b) adding 3-hydroxy-2-naphthoic acid or L-pyroglutamic acid or 2- methoxybenzoic acid, and
c) isolating the acid addition salt of Lamivudine Formula III.
2 The process according to claim 1, wherein said solvent is selected from ethanol, methanol, 1-propanol, 2-propanol, N, N-dimethylformamide, tetrahydrofuran, water or mixture thereof.
3 The process according to claim 1, wherein said metallic borohydride is selected from sodium borohydride, potassium borohydride or lithium borohydride.
4 A process for the preparation of Lamivudine comprising the steps of:
a) reacting the compound of Formula III with a base in solvent and
b) isolating the Lamivudine.
5 The process according to the claim 4, wherein said solvent is selected from acetone, methyl isobutyl ketone, methanol, ethanol, 2-propanol, tetrahydrofuran, dioxane, ethyl acetate, water or mixture thereof.
6 The process according to the claim 4, wherein said base is selected from ammonia, triethylamine or Hunig's base.
A process for the preparation of Lamivudine Form-I comprising the steps of:
a) dissolving Lamivudine in a mixture of solvents,
b) optionally removing the solvent,
c) cooling the resultant solution, and
d) isolating the Lamivudine Form-I.
11 The process according to the claim 10, wherein said solvent mixture is selected from aqueous isopropyl alcohol, aqueous methanol or aqueous ethanol.
12 A process for the preparation of Lamivudine Form-II comprising the steps of:
a) suspending Lamivudine in solvent,
b) removing the solvent,
c) cooling the resultant solution, and
d) isolating the Lamivudine Form-II.
13 The process according to claim 12, wherein said solvent is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, water or mixture thereof.
14 The process according to claim 10 and 12, wherein said solvent is removed by distillation or evaporation.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK10809247.9T DK2488516T3 (en) | 2009-10-14 | 2010-10-13 | Method of producing lamivudine and novel salts in the preparation thereof |
ES10809247.9T ES2540074T3 (en) | 2009-10-14 | 2010-10-13 | Process for the preparation of lamivudine and new salts in its manufacture |
EP10809247.9A EP2488516B1 (en) | 2009-10-14 | 2010-10-13 | Process for the preparation of lamivudine and novel salts in the manufacture thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2492CH2009 | 2009-10-14 | ||
IN2492/CHE/2009 | 2009-10-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2011045815A2 true WO2011045815A2 (en) | 2011-04-21 |
WO2011045815A3 WO2011045815A3 (en) | 2011-06-23 |
Family
ID=43827695
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2010/000679 WO2011045815A2 (en) | 2009-10-14 | 2010-10-13 | Process for the preparation of lamivudine and novel salts in the manufacture thereof |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP2488516B1 (en) |
DK (1) | DK2488516T3 (en) |
ES (1) | ES2540074T3 (en) |
WO (1) | WO2011045815A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004112735A1 (en) | 2003-06-17 | 2004-12-29 | Takasago International Corporation | Shampoo and body detergent composition |
CN102796089A (en) * | 2012-08-16 | 2012-11-28 | 江苏科本医药化学有限公司 | Preparation method of lamivudine intermediate and lamivudine |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5047407A (en) | 1989-02-08 | 1991-09-10 | Iaf Biochem International, Inc. | 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties |
US5905082A (en) | 1991-06-03 | 1999-05-18 | Glaxo Group Limited | Crystalline oxathiolane derivatives |
US6051709A (en) | 1994-04-23 | 2000-04-18 | Glaxo Group Limited | Process for the diastereoselective synthesis of nucleoside analogues |
WO2007119248A1 (en) | 2006-04-18 | 2007-10-25 | Lupin Limited | A novel crystalline form of lamivudine |
WO2008114279A2 (en) | 2007-03-19 | 2008-09-25 | Matrix Laboratories Ltd | Novel polymorphs of lamivudine |
WO2009037538A2 (en) | 2007-09-17 | 2009-03-26 | Aurobindo Pharma Ltd | Process for the preparation of lamivudine form i |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2227465A1 (en) * | 2007-11-29 | 2010-09-15 | Ranbaxy Laboratories Limited | Crystalline form i of lamivudine and its preparation |
-
2010
- 2010-10-13 WO PCT/IN2010/000679 patent/WO2011045815A2/en active Application Filing
- 2010-10-13 ES ES10809247.9T patent/ES2540074T3/en active Active
- 2010-10-13 EP EP10809247.9A patent/EP2488516B1/en not_active Not-in-force
- 2010-10-13 DK DK10809247.9T patent/DK2488516T3/en active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5047407A (en) | 1989-02-08 | 1991-09-10 | Iaf Biochem International, Inc. | 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties |
US5905082A (en) | 1991-06-03 | 1999-05-18 | Glaxo Group Limited | Crystalline oxathiolane derivatives |
US6051709A (en) | 1994-04-23 | 2000-04-18 | Glaxo Group Limited | Process for the diastereoselective synthesis of nucleoside analogues |
WO2007119248A1 (en) | 2006-04-18 | 2007-10-25 | Lupin Limited | A novel crystalline form of lamivudine |
WO2008114279A2 (en) | 2007-03-19 | 2008-09-25 | Matrix Laboratories Ltd | Novel polymorphs of lamivudine |
WO2009037538A2 (en) | 2007-09-17 | 2009-03-26 | Aurobindo Pharma Ltd | Process for the preparation of lamivudine form i |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004112735A1 (en) | 2003-06-17 | 2004-12-29 | Takasago International Corporation | Shampoo and body detergent composition |
CN102796089A (en) * | 2012-08-16 | 2012-11-28 | 江苏科本医药化学有限公司 | Preparation method of lamivudine intermediate and lamivudine |
CN102796089B (en) * | 2012-08-16 | 2015-06-17 | 江苏科本医药化学有限公司 | Preparation method of lamivudine intermediate and lamivudine |
Also Published As
Publication number | Publication date |
---|---|
WO2011045815A3 (en) | 2011-06-23 |
ES2540074T3 (en) | 2015-07-08 |
EP2488516A2 (en) | 2012-08-22 |
EP2488516B1 (en) | 2015-04-01 |
DK2488516T3 (en) | 2015-05-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8981105B2 (en) | Process of preparing a thrombin specific inhibitor | |
JP2013505259A5 (en) | ||
EP2590943B1 (en) | Process and intermediates for preparation of an active ingredient | |
US10358423B2 (en) | Processes for the preparation of 4-alkoxy-3-(acyl or alkyl)oxypicolinamdes | |
WO2014020555A2 (en) | An improved process for the preparation of dabigatran etexilate mesylate | |
EP3313841A1 (en) | Process for the preparation of a xanthine-based compound | |
CN109496210A (en) | His polymorphic and preparation method thereof of Baily department | |
US9834561B2 (en) | Process for preparing ibrutinib and its intermediates | |
JP2013216655A (en) | Improved preparation method of blonanserin | |
US20140187568A1 (en) | Crystalline forms of bosentan salts and processes for their preparation | |
EP2488516A2 (en) | Process for the preparation of lamivudine and novel salts in the manufacture thereof | |
US8952148B2 (en) | Process for the preparation of taurolidine and its intermediates thereof | |
WO2011095987A1 (en) | Novel process for the preparation of cis-nucleoside derivative | |
CN112645889A (en) | Refining method of Favipiravir | |
KR100995882B1 (en) | Process for preparing intermediate of pitavastatin or its salt | |
KR100881890B1 (en) | Process for preparation of Sarpogrelate HCl salt | |
CZ2009417A3 (en) | Novel process for preparing 2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-(1H-pyrrol-1-yl) 1H-benzimidazole (ilaprazole) | |
TW200302821A (en) | Process for production of optically active 2-halogeno-carboxylic acids | |
WO2013080095A1 (en) | Process for the preparation of agomelatine | |
WO2018130942A1 (en) | A process for the preparation of phenoxybenzamine | |
JP2007230906A (en) | Method for preparing n, n-dimethylcarbamoylmethyl 4-hydroxyphenylacetate | |
WO2013054273A2 (en) | Process for the preparation of agomelatine | |
CN118206567A (en) | Preparation method of fused ring compound | |
KR20110134249A (en) | Process for preparing intermediate of pitavastatin or its salt | |
JPWO2002070482A1 (en) | Method for producing optically active N-aryl-1-amino-2-propanol derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10809247 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010809247 Country of ref document: EP |
|
NENP | Non-entry into the national phase in: |
Ref country code: DE |