WO2007017720A1 - Process for the preparation of acitretin - Google Patents
Process for the preparation of acitretin Download PDFInfo
- Publication number
- WO2007017720A1 WO2007017720A1 PCT/IB2006/002098 IB2006002098W WO2007017720A1 WO 2007017720 A1 WO2007017720 A1 WO 2007017720A1 IB 2006002098 W IB2006002098 W IB 2006002098W WO 2007017720 A1 WO2007017720 A1 WO 2007017720A1
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- WO
- WIPO (PCT)
- Prior art keywords
- acitretin
- substantially pure
- solvent
- salt
- mixtures
- Prior art date
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- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 title claims abstract description 74
- 229960005339 acitretin Drugs 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229910003002 lithium salt Inorganic materials 0.000 claims description 7
- 159000000002 lithium salts Chemical class 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 150000004292 cyclic ethers Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 229910052712 strontium Inorganic materials 0.000 claims description 2
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 4
- 239000002253 acid Substances 0.000 claims 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 3
- 239000011707 mineral Substances 0.000 claims 3
- 239000003960 organic solvent Substances 0.000 claims 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims 1
- 239000000725 suspension Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000003556 assay Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940072291 soriatane Drugs 0.000 description 2
- IQVFBTXBSHRQAK-UHFFFAOYSA-N 3,7-dimethylnona-2,4,6,8-tetraenoic acid Chemical compound C=CC(C)=CC=CC(C)=CC(O)=O IQVFBTXBSHRQAK-UHFFFAOYSA-N 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- -1 aliphatic ethers Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 150000005672 tetraenes Chemical group 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
Definitions
- the present invention generally relates to a process for the preparation of substantially pure acitretin.
- 3,7-dimethyl-2,4,6,8-nonatetraenoic acid can be represented by the structure of Formula I.
- Acitretin an aromatic analogue of retinoic acid
- retinol vitamin A
- the tetraene side chain in acitretin exists in all-trans (or E) configuration.
- Acitretin is indicated for the treatment of severe psoriasis in adults and is marketed under the trade name Soriatane ® . See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 110, monograph 114; and Physician's Desk Reference, "Soriatane,” 60th Edition, pp. 1028-1035 (2005).
- U.S. Patent No. 4,105,681 discloses processes for the preparation of acitretin.
- Each of the processes in the '681 patent employ a Wittig reaction or its modification such as a Wittig-Horner procedure and provides a mixture of stereoisomers.
- Attempts at preparing acitretin of the desired purity by following the processes taught in Examples 1-3 of the '681 patent were unsuccessful. See, e.g., U.S. Patent Application Publication No. 2004/0192949.
- a similar Wittig process has been illustrated in Example 6 of DE 2636879 which provided only 47% of the all trans-isomer along with 51% of the 11-cis isomer, as an impurity.
- U.S. Patent Application Publication No. 2004/0192949 further discloses the purification of acitretin by contacting crude acitretin with one or more solvent, optionally in the presence of a free radical scavenger, and isolating substantially pure acitretin from a mixture thereof.
- a drawback associated with this process is it is commercially not suitable because of the instability of acitretin in most of the solvents.
- a lithium salt of acitretin is provided.
- the process of the present invention overcomes the problems associated with the prior art and provides a practical process for the preparation of substantially pure acitretin from a complex mixture of cis-trans isomers involving solvent treatment.
- the process of the present invention also advantageously avoids the tedious and cumbersome purification process pf column chromatography and has benefits with respect to economics and convenience to operate on a commercial scale.
- the present invention is directed to a process for the preparation of substantially pure acitretin of Formula I.
- the process of the present invention includes at least (a) contacting a salt of crude acitretin with one or more solvents; and (b) isolating substantially pure acitretin from the product of step (a).
- a salt of crude acitretin is contacted with one or more solvents to provide a substantially pure salt of acitretin.
- Useful salts of acitretin include, but are not limited to, sodium, lithium, magnesium, potassium, strontium, magnesium, barium, calcium and the like.
- the term "crude acitretin” as used herein shall be understood to mean acitretin containing a mixture of various cis-trans isomers as impurities. Crude acitretin is well known and may be obtained by any of the synthetic routes described in the prior art.
- Suitable solvents for use in step (a) include, but are not limited to, ketones, alcohols, cyclic ethers, aliphatic ethers, nitriles, esters, water, alkanes, and the like and mixtures thereof.
- Useful ketones include, but are not limited to, acetone, methyl isobutyl ketone, and the like and mixtures thereof.
- Useful alcohols include, but are not limited to, methanol, ethanol, isopropanol, and the like and mixtures thereof.
- Useful cyclic ethers include, but are not limited to, tetrahydrofuran, dioxane, and the like and mixtures thereof.
- Useful nitriles include, but are not limited to, acetonitrile and the like and mixtures thereof.
- Useful esters include, but are not limited to, ethyl acetate, and the like and mixtures thereof.
- Useful alkanes include, but are not limited to, n-hexane, heptane and the like and mixtures thereof.
- substantially pure salt of crude acitretin can precipitate out of the solution and then optionally recovered by, for example, filtration.
- substantially pure salt of acitretin shall be understood to mean a salt of acitretin having an assay of greater than or equal to about 98% as determined by high performance liquid chromatography (HPLC).
- the product substantially pure acitretin can be isolated from the substantially pure salt of acitretin by, for example, acidifying, cooling, filtering, or a combination thereof.
- substantially pure acitretin shall be understood to mean acitretin having an assay of greater than or equal to about 98% as determined by HPLC and preferably greater than or equal to about 99%.
- Step I Process for Salt Preparation and Purification.
- Step II Process for Isolation of Acitretin
- step I The substantially pure sodium salt of acitretin obtained in step I was added in water (80 ml) and acidified with 30% HCl and stirred for 30 minutes at 25 to 3O 0 C to obtain a suspension. The suspension was then filtered, washed with water and dried at 25- 3O 0 C to obtain substantially pure acitretin (7 g, assay 99.45% as determined by HPLC).
- Step I Process for Salt Preparation and Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the preparation of substantially pure acitretin of Formula (I) is provided: the process comprising (a) contacting a salt of acitretin with one or more solvents; and (b) isolating substantially pure acitretin from the product of step (a).
Description
PROCESS FOR THE PREPARATION OF ACITRETIN
PRIORITY
[0001] This application claims the benefit under 35 U.S.C. §119 to U.S.
Provisional Application No. 60/716,734, filed on September 13, 2005, and entitled "PROCESS FOR THE PREPARATION OF ACITRETIN", and to Indian Provisional Application No. 914/MUM/2005, filed on August 5, 2005, and entitled "PROCESS FOR THE PREPARATION OF ACITRETIN", the contents of each of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
[0002] The present invention generally relates to a process for the preparation of substantially pure acitretin.
2. Description of the Related Art
[0003] Acitretin, also known as (all-trans)-9-(4-methoxy-2,3,6-trimethylphenyl)-
3,7-dimethyl-2,4,6,8-nonatetraenoic acid, can be represented by the structure of Formula I.
Acitretin, an aromatic analogue of retinoic acid, is a member of the retinoid family, a group of compounds related to retinol (vitamin A). The tetraene side chain in acitretin exists in all-trans (or E) configuration. Acitretin is indicated for the treatment of severe psoriasis in adults and is marketed under the trade name Soriatane®. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 110, monograph 114; and Physician's Desk Reference, "Soriatane," 60th Edition, pp. 1028-1035 (2005).
[0004] U.S. Patent No. 4,105,681 ("the '681 patent") discloses processes for the preparation of acitretin. Each of the processes in the '681 patent employ a Wittig reaction or its modification such as a Wittig-Horner procedure and provides a mixture of stereoisomers. Attempts at preparing acitretin of the desired purity by following the
processes taught in Examples 1-3 of the '681 patent were unsuccessful. See, e.g., U.S. Patent Application Publication No. 2004/0192949. A similar Wittig process has been illustrated in Example 6 of DE 2636879 which provided only 47% of the all trans-isomer along with 51% of the 11-cis isomer, as an impurity.
[0005] U.S. Patent Application Publication No. 2004/0192949 further discloses the purification of acitretin by contacting crude acitretin with one or more solvent, optionally in the presence of a free radical scavenger, and isolating substantially pure acitretin from a mixture thereof. However, a drawback associated with this process is it is commercially not suitable because of the instability of acitretin in most of the solvents. [0006] In light of the above drawbacks in the prior art processes, there is a need for the development of a simple and efficient process for the preparation of the desired all trans-isomer of 9-(4-methoxy-253,6-trimethyl phenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid (acitretin) in relatively high purity. It would also be desirable to provide a process for preparing substantially pure acitretin from a complex mixture of cis-trans isomers.
SUMMARY OF THE INVENTION
[0007] In accordance with one embodiment of the present invention, a process for the preparation of substantially pure acitretin of Formula I is provided:
[0008] In accordance with a second embodiment of the present invention, a lithium salt of acitretin is provided.
[0009] The process of the present invention overcomes the problems associated with the prior art and provides a practical process for the preparation of substantially pure acitretin from a complex mixture of cis-trans isomers involving solvent treatment. The process of the present invention also advantageously avoids the tedious and cumbersome
purification process pf column chromatography and has benefits with respect to economics and convenience to operate on a commercial scale.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0010] The present invention is directed to a process for the preparation of substantially pure acitretin of Formula I.
The process of the present invention includes at least (a) contacting a salt of crude acitretin with one or more solvents; and (b) isolating substantially pure acitretin from the product of step (a).
[0011] In step (a) of the process of the present invention, a salt of crude acitretin is contacted with one or more solvents to provide a substantially pure salt of acitretin. Useful salts of acitretin include, but are not limited to, sodium, lithium, magnesium, potassium, strontium, magnesium, barium, calcium and the like. The term "crude acitretin" as used herein shall be understood to mean acitretin containing a mixture of various cis-trans isomers as impurities. Crude acitretin is well known and may be obtained by any of the synthetic routes described in the prior art.
[0012] Suitable solvents for use in step (a) include, but are not limited to, ketones, alcohols, cyclic ethers, aliphatic ethers, nitriles, esters, water, alkanes, and the like and mixtures thereof. Useful ketones include, but are not limited to, acetone, methyl isobutyl ketone, and the like and mixtures thereof. Useful alcohols include, but are not limited to, methanol, ethanol, isopropanol, and the like and mixtures thereof. Useful cyclic ethers include, but are not limited to, tetrahydrofuran, dioxane, and the like and mixtures thereof. Useful nitriles include, but are not limited to, acetonitrile and the like and mixtures thereof. Useful esters include, but are not limited to, ethyl acetate, and the like and mixtures thereof. Useful alkanes include, but are not limited to, n-hexane, heptane and the like and mixtures thereof.
[0013] The step of contacting the salt of crude acitretin with one or more solvents to provide a substantially pure salt of acitretin can be accomplished by, for example, stirring, slurrying, dissolving or a combination thereof the salt of crude acitretin and the one or more solvent. In this step, the substantially pure salt of crude acitretin can precipitate out of the solution and then optionally recovered by, for example, filtration. The term "substantially pure salt of acitretin" as used herein shall be understood to mean a salt of acitretin having an assay of greater than or equal to about 98% as determined by high performance liquid chromatography (HPLC).
[0014] In step (b) of the process of the present invention, the product substantially pure acitretin can be isolated from the substantially pure salt of acitretin by, for example, acidifying, cooling, filtering, or a combination thereof. The term "substantially pure acitretin" as used herein shall be understood to mean acitretin having an assay of greater than or equal to about 98% as determined by HPLC and preferably greater than or equal to about 99%.
[0015] As one skilled in the art will readily appreciate, the steps of contacting and isolating in the process of the present invention may be repeated to achieve the desired results.
[0016] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
Experimental
[0017] The purity was measured by high performance liquid chromatography under the following conditions:
Column: Lichrosphere PAH, 250 X 4.0 mm, 5μ or equivalent
Moving phase: 0.3% v/v solution of glacial acetic acid R in a mixture of 8 volumes of water R and 92 volumes of ethanol R, wherein R means reagent grade
Detector: UV, 360 nm
Flow rate: 0.6 ml/minute
Retention time: 6.2 minutes
EXAMPLE 1.
[0018] Step I: Process for Salt Preparation and Purification.
[0019] Crude acitretin (10 g) was dissolved in tetrahydrofuran (220 ml). Next, an aqueous sodium hydroxide solution (8 ml, 50%) was added to the solution and stirred at 25-3O0C for 6 hours. The suspension was then filtered to obtain a wet cake of a sodium salt of acitretin. Next, the wet cake of the sodium salt of acitretin was added in acetone (50 ml) and stirred at 25-3O0C for 1 hour. The suspension was then filtered, washed with acetone ( 20 ml) and dried under vacuum at 25-300C for 4 hours to obtain a substantially pure sodium salt of acitretin (7.7 g, purity 99.5 % as determined by HPLC ). [0020] Step II: Process for Isolation of Acitretin
[0021] The substantially pure sodium salt of acitretin obtained in step I was added in water (80 ml) and acidified with 30% HCl and stirred for 30 minutes at 25 to 3O0C to obtain a suspension. The suspension was then filtered, washed with water and dried at 25- 3O0C to obtain substantially pure acitretin (7 g, assay 99.45% as determined by HPLC).
EXAMPLE 2
[0022] Step I: Process for Salt Preparation and Purification
[0023] Crude acitretin (10 g) was dissolved in tetrahydrofuran (200 ml). An aqueous lithium hydroxide solution (8 ml, 50%) was added to the solution and stirred at 25-300C for 6 hours. Next, tetrahydrofuran was distilled out completely at 25-300C under vacuum and acetone (50 ml) was added and stirred at 25-3O0C for 1 hour to obtain a suspension. The suspension was then filtered, washed with acetone (20 ml) and dried under vacuum at 25-300C for 4 hours to obtain a substantially pure lithium salt of acitretin (7.3 g, purity 98.5 % as determined by HPLC ). [0024] Step II: Process for Isolation of Acitretin
[0025] The substantially pure lithium salt of acitretin obtained in step II was added in water (80 ml) and acidified with 30% HCl and stirred for 30 minutes at 25-300C to obtain a suspension. The suspension was then filtered, washed with water and dried at 25- 3O0C to obtain substantially pure acitretin (6.7 g, assay 98.5% as determined by HPLC).
[0026] While the above description contains many specifics, these specifics should not be construed as limitations of the invention, but merely as exemplifications of preferred embodiments thereof. Those skilled in the art will envision many other embodiments within the scope and spirit of the invention as defined by the features and advantages appended hereto.
Claims
1. A process for the preparation of substantially pure acitretin of Formula I:
2. The process of Claim 1, wherein the salt of crude acitretin is sodium, potassium, magnesium, strontium, lithium, calcium or barium.
3. The process of Claims 1 and 2, wherein the solvent is selected from the group consisting of a ketone, alcohol, ether, ester, water, nitrile, alkane and mixtures thereof.
4. The process of Claim 3, wherein the ketone solvent is selected from the group consisting of acetone, methyl isobutyl ketone and mixtures thereof.
5. The process of Claim 3, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof.
6. The process of Claim 3, wherein the ether solvent is a cyclic ether selected from the group consisting of tetrahydrofuran, dioxane and mixtures thereof.
7. The process of Claim 3, wherein the nitrile solvent is acetonitrile.
8. The process of Claim 3, wherein the ester solvent is ethyl acetate.
9. The process of Claim 3, wherein the alkane solvent is selected from the group consisting of n-hexane, heptane and mixtures thereof.
10. The process of Claims 1 and 2, wherein the solvent is selected from the group consisting of an acetone, methanol, tetrahydrofuran, acetonitrile, ethyl acetate, water, n- hexane and mixtures thereof.
11. The process of Claims 1-10, wherein the step of contacting comprises stirring the salt of crude acitretin and the one or more solvent.
12. The process of Claims 1-10, wherein the step of contacting comprises slurrying the salt of crude acitretin and the one or more solvent.
13. The process of Claims 1-10, wherein the step of contacting comprises dissolving the salt of crude acitretin and the one or more solvent.
14. The process of Claims 1-13, wherein the step of isolating the substantially pure acitretin comprises acidifying the substantially pure salt of acitretin.
15. The process of Claim 14, wherein the substantially pure salt of acitretin is acidified with a mineral acid in an organic solvent.
16. The process of Claim 15, wherein the mineral acid is hydrochloric acid.
17. The process of Claim 15, wherein the mineral acid is aqueous hydrochloric acid.
18. The process of Claims 15-17, wherein the organic solvent is water.
19. The process of Claims 1-18, wherein the substantially pure acitretin isolated in step (b) has a purity of greater than or equal to about 98%.
20. The process of Claims 1-18, wherein the substantially pure acitretin isolated in step (b) has a purity of greater than or equal to about 99%.
21. A lithium salt of acitretin.
22. Substantially pure lithium salt of acitretin.
23. Substantially pure lithium salt of acitretin having a purity of greater than or equal to about 98%.
24. Substantially pure lithium salt of acitretin having a purity of greater than or equal to about 99%.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN914/MUM/2005 | 2005-08-05 | ||
| IN914MU2005 | 2005-08-05 | ||
| US71673405P | 2005-09-13 | 2005-09-13 | |
| US60/716,734 | 2005-09-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007017720A1 true WO2007017720A1 (en) | 2007-02-15 |
Family
ID=37497037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2006/002098 WO2007017720A1 (en) | 2005-08-05 | 2006-08-02 | Process for the preparation of acitretin |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2007017720A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2067764A1 (en) | 2007-11-07 | 2009-06-10 | SOLMAG S.p.A. | Process for the preparation of pure acitretin |
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| US4105681A (en) * | 1975-08-01 | 1978-08-08 | Hoffmann-La Roche Inc. | 9-phenyl 5,6-dimethyl-nona-2,4,6,8-tetraeonic acid compounds |
| WO2003007871A2 (en) * | 2001-07-19 | 2003-01-30 | Ranbaxy Laboratories Limited | Process for the preparation of acitretin |
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- 2006-08-02 WO PCT/IB2006/002098 patent/WO2007017720A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4105681A (en) * | 1975-08-01 | 1978-08-08 | Hoffmann-La Roche Inc. | 9-phenyl 5,6-dimethyl-nona-2,4,6,8-tetraeonic acid compounds |
| WO2003007871A2 (en) * | 2001-07-19 | 2003-01-30 | Ranbaxy Laboratories Limited | Process for the preparation of acitretin |
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| Title |
|---|
| DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PAN, MINGXIN ET AL: "Method for purifying Acitretin A", XP002412846, retrieved from STN Database accession no. 2006:1112693 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2067764A1 (en) | 2007-11-07 | 2009-06-10 | SOLMAG S.p.A. | Process for the preparation of pure acitretin |
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