WO2016116073A1 - Chiral resolution of bedaquiline by using cyclcic phosphoric acids - Google Patents
Chiral resolution of bedaquiline by using cyclcic phosphoric acids Download PDFInfo
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- WO2016116073A1 WO2016116073A1 PCT/CZ2016/000003 CZ2016000003W WO2016116073A1 WO 2016116073 A1 WO2016116073 A1 WO 2016116073A1 CZ 2016000003 W CZ2016000003 W CZ 2016000003W WO 2016116073 A1 WO2016116073 A1 WO 2016116073A1
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- mixture
- rac
- propanediol
- phenyl
- hydrogen phosphate
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- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical compound C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-XLJNKUFUSA-N 0.000 title claims abstract description 51
- 229960000508 bedaquiline Drugs 0.000 title claims abstract description 46
- 150000003016 phosphoric acids Chemical class 0.000 title description 2
- 235000011007 phosphoric acid Nutrition 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 56
- 238000002955 isolation Methods 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 22
- HYCSHFLKPSMPGO-UHFFFAOYSA-N 3-hydroxypropyl dihydrogen phosphate Chemical class OCCCOP(O)(O)=O HYCSHFLKPSMPGO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 3
- 239000000470 constituent Substances 0.000 claims abstract 2
- 238000000746 purification Methods 0.000 claims abstract 2
- 238000002425 crystallisation Methods 0.000 claims description 26
- 230000008025 crystallization Effects 0.000 claims description 26
- QUIJNHUBAXPXFS-CDZUIXILSA-N (1s,2r)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol Chemical compound C1([C@@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-CDZUIXILSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- 238000010992 reflux Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- 238000011081 inoculation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 4
- UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 0 *[C@]([C@@](*)(c1cccc2c1cccc2)O)(c1ccccc1)c1cc2cc(Br)ccc2nc1* Chemical compound *[C@]([C@@](*)(c1cccc2c1cccc2)O)(c1ccccc1)c1cc2cc(Br)ccc2nc1* 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- ZBDLNWGDORWUTB-UHFFFAOYSA-N 1-[2-bromo-6-(2-methoxyquinolin-3-yl)phenyl]-4-(dimethylamino)-2-naphthalen-1-ylbutan-2-ol Chemical compound BrC1=CC=CC(=C1CC(CCN(C)C)(O)C1=CC=CC2=CC=CC=C12)C=1C(=NC2=CC=CC=C2C=1)OC ZBDLNWGDORWUTB-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001197925 Theila Species 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
Definitions
- the invention relates to isolation of a solid form of (li -; 25)-l-(6-bromo-2-methoxyquinolin-3- yl)-4-dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol of formula la,
- (la) known as bedaquiline. Bedaquiline is isolated from a mixture of the corresponding stereoisomers (la - (li -; 2S)-(6-bromo-2-me&oxy-quinolin-3-yl)-4-dimethylamino-2-(l- naphthyl)-l-phenyl-butan-2-ol, lb - (liS,2i?)-(6-bromo-2-memoxy-qumolin-3-yl)-4- dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol, Ila - (lS,2S)-(6-bromo-2-methoxy- qumolm-3-yl)-4-dimemylainino-2-(l-naphtiiyl)-l-phenyl-butan-2-ol, lib - (lii ⁇ ii)-(6-bromo- 2-
- Ills Illr la ( 1 J R,2S)-(6-Bromo-2-methoxy-quinolin-3 -yl)-4-dimethylamino-2-( 1 -naphthy 1)- 1 -phenyl-butan-2-ol lb: (1 S',2R)-(6-Bromo-2-me1hoxy-quinoHn-3-yl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan-2-ol Ha: ( lS,2S)-(6-Bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan-2-ol lib: (1 R,2R)-(6-Bromo-2-methoxy-quinolin-3 -yl)-4-dimethylamino-2-( 1 -n
- (1 R,2S)- 1 -(6-Bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-(l -naphthyl)- 1 -phenyl- butan-2-ol la which is known as bedaquiline (CAS no. 843663-66-1), belongs to the group of quinoline derivatives that can be used as microbial inhibitors.
- the chiral purity of the product and reaction yield are influenced by the reaction conditions and selection of the chiral agent used for the crystallization. It is obvious that for the preparation of bedaquiline with a high reaction yield, chemical and chiral purity suitable chiral substances and optimal reaction (crystallization) conditions must be used.
- the invention provides isolation of bedaquiline from a mixture of stereoisomers containing the I-rac isomers, possibly with admixed Il-rac, I-rac and Il-rac being in any ratio, with the use of chiral derivatives of 1,3 -propanediol hydrogen phosphate (general formula IV) and methods of its isolation.
- the isolation is carried out by crystallization of a salt of bedaquiline la with the selected chiral derivative of 1,3-propanediol-hydrogen phosphate IV in a suitable solvent or mixtures of solvents.
- R ls R 2 ⁇ and R3 independently stand for hydrogen, a halogen, C C 6 alkyl, aryl, naphthyl, phenyl, and preferably a halogenated phenyl or phenyl substituted in any way.
- the invention provides isolation of bedaquiline from a mixture of stereoisomers containing the I-rac isomers, possibly with admixed Il-rac, I-rac and Il-rac being in any ratio.
- the content of I-rac in the mixture with Il-rac is 60 to 100%.
- the method brings very good results e.g. with the content of I-rac of 80% and more.
- the isolation is carried out with the use of crystallization with 1,3-propanediol hydrogen phosphate IV and its chiral derivatives as the crystallization agent; and methods of performing the same.
- a suitable chiral agent one can mention the use of (i?)-(+)-l-(2-methoxyphenyl)-l,3- propanediol-2,2-dimethyl hydrogen phosphate (CAS RK: 98674-82-9; formula V), or (£)-(+)- l-(2-chlorophenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate (CAS RN: 98674-87-4; formula VI).
- the isolated solid form of bedaquiline may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of its isolation. For this reason, the invention relates to isolation of bedaquiline with the use of derivatives of 1,3-propanediol hydrogen phosphate under various conditions with the use of a number of common solvents or their mixtures.
- the described isolation procedures are suitable for isolation of bedaquiline la in a solid form with high chemical and optical purity; they can be easily transferred into the industrial scale to provide a sufficient amount of bedaquiline for commercial use.
- Isolation of bedaquiline la is carried out by means of crystallization of the bedaquiline isomers Ia-b, Ila-b with derivatives of 1,3-propanediol hydrogen phosphate in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles, or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water and/or their mixtures. Aliphatic C - C 4 alcohols, esters or their mixtures are preferred.
- the most commonly used solvents are ethanol, isopropanol, acetonitrile, tetrahydrofuran or their mixtures.
- the resulting diastereoisomeric salt of bedaquiline la is precipitated or crystallized, typically at temperatures in the range of -30°C to the boiling point of the solvent.
- Bedaquiline la can be isolated from the racemic mixture I-rac in a solid form by means of chiral HPLC (WO 2004/011436) or with the use of (-3 ⁇ 4)-(-)-l J l'-binaphthyl-2.2'-diyl hydrogen phosphate (WO 2006/125769).
- chiral HPLC WO 2004/011436
- chiral derivatives of 1,3 -propanediol hydrogen phosphate for isolation of bedaquiline as the chiral crystallization agent in a suitable solvent or a mixture of solvents.
- Example 8 (below in this description) can be compared to the result of Example 1 in the cited document. Both the methods were carried out with comparable ratios, i.e. I-rac : II-rac is about 11 : 2. According to Example 1 of WO 2006/125769, 63% of all bedaquiline contained in the mixture was crystallized in this way. Our method, as demonstrated in our Example 8, provided 95% of all bedaquiline. Thus, the separation in accordance with this invention is more efficient than the methods described so far.
- the free base of bedaquiline la can be released from the given diastereoisomeric salt with the use of a suitable base, e.g. a carbonate or phosphate base.
- a suitable base e.g. a carbonate or phosphate base.
- K 2 C0 3 , KHC0 3 , Na 2 C0 3 , NaHC0 3 , Na 3 P0 4 , or Na 2 HP0 4 can be preferably used.
- extraction of the free base with the use of toluene or Me-THF and an aqueous solution of K 2 C0 3 can be mentioned, wherein bedaquiline la can be isolated as a solid substance after releasing of the base in the organic layer, which can be separated, and after its evaporation.
- Crystallization yield 75.6 mg (52.3 %).
- the solid fraction obtained by filtration contained the salt of (15 r ,2i-)-l-(6-bromo-2-memoxyquinolm-3-yl)-4-dimemylamino-2-(l- naphthyl)-l-phenyl-butan-2-ol lb with (i-)-(-)-l-(2-phenyl)-l 5 3-propanediol-2,2-dimethyl hydrogen phosphate with the chiral purity of 99.9%.
- the mother liquor was evaporated with the use of a vacuum evaporator and the obtained solid matter was re-dried in a vacuum drier at 40°C for 16 hours.
- the evaporation of the mother liquor provided 68.9 mg (47.7%) of solid matter representing the diastereoisomeric salt la with (jR)-(-)-l-(2-phenyl)-l,3-propanediol-2,2-dimetihyl hydrogen phosphate Illr with the chiral purity of 95%.
- Crystallization yield 73.6 mg (50.9%).
- the solid fraction obtained by filtration contained the salt of (lS J 2 J R)-l-(6-bromo-2-memoxyquinomi-3-yl)-4-dimemylarnino-2-(l- naphthyl)-l-phenyl-butan-2-ol lb and (i?)-(-)-l-(2-phenyl)-l 5 3-propanediol-2,2-dimethyl hydrogen phosphate Illr with the chiral purity of 99.7%.
- the mother liquor was evaporated with the use of a vacuum evaporator and the obtained solid matter was re-dried in a vacuum drier at 40°C for 16 hours.
- the evaporation of the mother liquor provided 70.9 mg (49.1%) of solid matter representing the diastereoisomeric salt la with (i-)-(-)-l-(2-phenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate Illr with the chiral purity of 96.6%.
- Crystallization yield 72.1 mg (49.5%).
- the solid fraction obtained by filtration contained the salt of bedaquiline la with ( ⁇ S)-(+)-l-(2-phenyl)-l ⁇ 3-propanediol-2,2- dimethyl hydrogen phosphate Ills (with the chiral purity of 99.6% (HPLC purity 98%)).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method of performing isolation and purification of bedaquiline (la) from a mixture of stereoisomers of 6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-(l-naphthyl)-l- phenyl-butan-2-ol identified as I-rac, being a mixture of the stereoisomers of formulae la, lb, and II-rac, being a mixture of the stereoisomers of formulae Ila, lib, with any ratio of individual constituents of the mixture, wherein said mixture is dissolved together with derivatives of 1,3 -propanediol hydrogen phosphate of formula IV, wherein R1, R2, and R3 independently stand for hydrogen, a halogen, C1-C6 alkyl, aryl, naphthyl, phenyl and preferably a halogenated phenyl or phenyl substituted in any way, and the resulting salt is crystallized.
Description
CHIRAL RESOLUTION OF BEDAQUILINE BY USING CYCLCIC PHOSPHORIC ACIDS
Technical Field The invention relates to isolation of a solid form of (li-;25)-l-(6-bromo-2-methoxyquinolin-3- yl)-4-dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol of formula la,
BEDAQUIUN
(la) known as bedaquiline. Bedaquiline is isolated from a mixture of the corresponding stereoisomers (la - (li-;2S)-(6-bromo-2-me&oxy-quinolin-3-yl)-4-dimethylamino-2-(l- naphthyl)-l-phenyl-butan-2-ol, lb - (liS,2i?)-(6-bromo-2-memoxy-qumolin-3-yl)-4- dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol, Ila - (lS,2S)-(6-bromo-2-methoxy- qumolm-3-yl)-4-dimemylainino-2-(l-naphtiiyl)-l-phenyl-butan-2-ol, lib - (lii^ii)-(6-bromo- 2-methoxy-quinolin-3-yl)-4-dimethylamino-2-(l-naphthyl)- l-phenyl-butan-2-ol), or the corresponding racemate I-rac (I-rac = mixture of the la : lb isomers in the 1:1 ratio) by means of crystallization with (S)-(+)-l -phenyl- 1 ,3 -propanediol-2,2-dimethyl hydrogen phosphate (formula Ills; CAS RN: 98674-81-8), or its derivatives, as a chiral crystallization agent.
Ills Illr la: ( 1 JR,2S)-(6-Bromo-2-methoxy-quinolin-3 -yl)-4-dimethylamino-2-( 1 -naphthy 1)- 1 -phenyl-butan-2-ol lb: (1 S',2R)-(6-Bromo-2-me1hoxy-quinoHn-3-yl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan-2-ol Ha: ( lS,2S)-(6-Bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan-2-ol lib: (1 R,2R)-(6-Bromo-2-methoxy-quinolin-3 -yl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -pheny l-butan-2- ol
I- rac = mixture of the la and lb isomers in the 1 : 1 ratio
II- rac = mixture of the Ila and lib isomers in the 1:1 ratio
Background Art
(1 R,2S)- 1 -(6-Bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-(l -naphthyl)- 1 -phenyl- butan-2-ol la, which is known as bedaquiline (CAS no. 843663-66-1), belongs to the group of quinoline derivatives that can be used as microbial inhibitors.
Preparation of this molecule and its use for the treatment of microbial diseases is described in a patent (WO 2004/011436). Bedaquiline was isolated from a diastereoisomeric mixture by means of chiral liquid chromatography. Isolation of bedaquiline from a mixture of the corresponding stereoisomers by means of crystallization with the chiral agent (ϋ)-(-)-1,Γ-
binaphthyl-2.2'-diyl hydrogen phosphate or its derivatives is described in a patent (WO 2006/125769).
The chiral purity of the product and reaction yield are influenced by the reaction conditions and selection of the chiral agent used for the crystallization. It is obvious that for the preparation of bedaquiline with a high reaction yield, chemical and chiral purity suitable chiral substances and optimal reaction (crystallization) conditions must be used.
Disclosure of Invention The invention provides isolation of bedaquiline from a mixture of stereoisomers containing the I-rac isomers, possibly with admixed Il-rac, I-rac and Il-rac being in any ratio, with the use of chiral derivatives of 1,3 -propanediol hydrogen phosphate (general formula IV) and methods of its isolation. The isolation is carried out by crystallization of a salt of bedaquiline la with the selected chiral derivative of 1,3-propanediol-hydrogen phosphate IV in a suitable solvent or mixtures of solvents.
(IV)
Rls R2} and R3 independently stand for hydrogen, a halogen, C C6 alkyl, aryl, naphthyl, phenyl, and preferably a halogenated phenyl or phenyl substituted in any way.
It has been unexpectedly found out that the derivatives of 1,3-propanediol-hydrogen phosphate IV used make it possible to isolate bedaquiline in a high yield, with a high chemical and enantiomeric purity. The described isolation procedures can be easily transferred into the industrial scale to obtain a sufficient amount of bedaquiline for commercial use.
Detailed description of the invention
The invention provides isolation of bedaquiline from a mixture of stereoisomers containing the I-rac isomers, possibly with admixed Il-rac, I-rac and Il-rac being in any ratio. In a preferred case the content of I-rac in the mixture with Il-rac is 60 to 100%. The method brings very good results e.g. with the content of I-rac of 80% and more. The isolation is carried out with
the use of crystallization with 1,3-propanediol hydrogen phosphate IV and its chiral derivatives as the crystallization agent; and methods of performing the same. As an example of a suitable chiral agent one can mention the use of (i?)-(+)-l-(2-methoxyphenyl)-l,3- propanediol-2,2-dimethyl hydrogen phosphate (CAS RK: 98674-82-9; formula V), or (£)-(+)- l-(2-chlorophenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate (CAS RN: 98674-87-4; formula VI).
Mr Vs Vlr Vis
Crystallization of mixtures of diastereoisomeric salts of the bedaquiline isomers Ia-b, Ila-b with 1,3-propanediol hydrogen phosphate and its derivatives makes it possible to isolate bedaquiline in a solid form in a high yield, with high chemical and enantiomeric purity.
The isolated solid form of bedaquiline may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of its isolation. For this reason, the invention relates to isolation of bedaquiline with the use of derivatives of 1,3-propanediol hydrogen phosphate under various conditions with the use of a number of common solvents or their mixtures.
The described isolation procedures are suitable for isolation of bedaquiline la in a solid form with high chemical and optical purity; they can be easily transferred into the industrial scale to provide a sufficient amount of bedaquiline for commercial use.
Isolation of bedaquiline la is carried out by means of crystallization of the bedaquiline isomers Ia-b, Ila-b with derivatives of 1,3-propanediol hydrogen phosphate in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles, or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water and/or their mixtures. Aliphatic C - C4 alcohols, esters or their mixtures are preferred. The most commonly used solvents are ethanol, isopropanol, acetonitrile, tetrahydrofuran or their mixtures.
The resulting diastereoisomeric salt of bedaquiline la is precipitated or crystallized, typically at temperatures in the range of -30°C to the boiling point of the solvent.
Preparation of a mixture of the stereoisomers of 6-bromo-2-methoxy-3-quinolyl-4- climemylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol Ia-b, Ila-b, isolation of the racemic mixture I-rac of (15,2i-)-l-(6-bromo-2-memoxyqumolm-3-yl)-4-dimemylarru^o-2-(l-
naphthyl)-l-phenyl-butan-2-ol and bedaquiline la ((li?,2S)-l-(6-bromo-2-methoxyquinolin-3- yl)-4-dime&ylammo-2-(l-naph^^ is described in a patent (WO
2004/011436).
Bedaquiline la can be isolated from the racemic mixture I-rac in a solid form by means of chiral HPLC (WO 2004/011436) or with the use of (-¾)-(-)-lJl'-binaphthyl-2.2'-diyl hydrogen phosphate (WO 2006/125769). In this invention it has been found out that it is possible to advantageously use chiral derivatives of 1,3 -propanediol hydrogen phosphate for isolation of bedaquiline as the chiral crystallization agent in a suitable solvent or a mixture of solvents. To compare the effect of the method in accordance with this invention and that of WO 2006/125769, the result of Example 8 (below in this description) can be compared to the result of Example 1 in the cited document. Both the methods were carried out with comparable ratios, i.e. I-rac : II-rac is about 11 : 2. According to Example 1 of WO 2006/125769, 63% of all bedaquiline contained in the mixture was crystallized in this way. Our method, as demonstrated in our Example 8, provided 95% of all bedaquiline. Thus, the separation in accordance with this invention is more efficient than the methods described so far.
The free base of bedaquiline la can be released from the given diastereoisomeric salt with the use of a suitable base, e.g. a carbonate or phosphate base. K2C03, KHC03, Na2C03, NaHC03, Na3P04, or Na2HP04 can be preferably used. As an example, extraction of the free base with the use of toluene or Me-THF and an aqueous solution of K2C03 can be mentioned, wherein bedaquiline la can be isolated as a solid substance after releasing of the base in the organic layer, which can be separated, and after its evaporation.
A crystalline form of the free base of bedaquiline with the melting point of 118°C is described in a patent (WO 2004/011436).
The invention is clarified in a more detailed way using the working examples below. These examples, which illustrate new possibilities of isolation of bedaquiline in a solid form in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.
Experimental part
High-performance liquid chromatography (HPLC)
Separation of the enantiomers of bedaquiline and verification of the optical purity of the products were carried out in an OJ-3R column, 150x4.6 mm ID, 3 μιη, with the use of the
triethylamine buffer pH 8 - acetonitrile (40+60) mobile phase at the flow rate of 1 ml/min and separation temperature of 35°C. The injection volume of the analyzed sample, which was dissolved in methanol to the concentration of 0.5 mg/ml, was 5 μΐ. Bedaquiline was detected by UV detection at 227 nm.
Examples Example 1
Preparation of a mixture of the stereoisomers of 6-bromo-2-methoxyquinolin-3-yl-4- dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol I-rac, II-rac was carried out in accordance with the procedure described in the patent WO 2006/125769 ("Step C").
Example 2
Preparation of the I-rac mixture was carried out in accordance with the procedure described in the patent WO 2004/011436 (Example B7).
Example 3
Isolation of the salt of bedaquiline la with (i-)-(-)-l-(2-phenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate Illr from ethanol
100 mg (1.80-10"4 mol) of the I-rac racemic mixture was dissolved in 13 ml of anhydrous ethanol under reflux. 44.5 mg (1.80-10"4 mol) of ( )-(-)- l-(2-phenyl)-l, 3 -propanediol-2,2- dimethyl hydrogen phosphate (98%) (CAS RN: 98674-80-7) was dissolved in 2.2 ml of ethanol and this solution was added to the solution of the diastereoisomeric mixture and left to be stirred under reflux for 10 minutes. After cooling of the solution to the room temperature with continuous stirring, solid matter separated, which was filtered and dried in a vacuum drier at 40°C for 16 hours. Inoculation of the solution with prepared crystallization inocula can also be used. Crystallization yield 75.6 mg (52.3 %). The solid fraction obtained by filtration contained the salt of (15r,2i-)-l-(6-bromo-2-memoxyquinolm-3-yl)-4-dimemylamino-2-(l- naphthyl)-l-phenyl-butan-2-ol lb with (i-)-(-)-l-(2-phenyl)-l53-propanediol-2,2-dimethyl hydrogen phosphate with the chiral purity of 99.9%.
After the filtration, the mother liquor was evaporated with the use of a vacuum evaporator and the obtained solid matter was re-dried in a vacuum drier at 40°C for 16 hours. The evaporation of the mother liquor provided 68.9 mg (47.7%) of solid matter representing the
diastereoisomeric salt la with (jR)-(-)-l-(2-phenyl)-l,3-propanediol-2,2-dimetihyl hydrogen phosphate Illr with the chiral purity of 95%.
Example 4
Isolation of the salt of bedaquiline la with (i?)-(-)-l-(2-phenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate Illr from the I-rac racemic mixture in isopropyl alcohol.
100 mg (1.80Ί0"4 mol) of the I-rac racemic mixture was dissolved in 13 ml of isopropyl alcohol under reflux. 44.5 mg (1.80-10"4 mol) of (i-)-(-)-l-(2 -phenyl)- l,3-propanediol-2,2- dimethyl hydrogen phosphate Illr (98%) (CAS RN: 98674-80-7) was dissolved in 2.2 ml of isopropyl alcohol and this solution was added to the solution of the racemic mixture and left to be stirred under reflux for 10 minutes. After cooling of the solution to the room temperature with continuous stirring, solid matter separated, which was filtered and dried in a vacuum drier at 40°C for 16 hours. Inoculation of the solution with prepared crystallization inocula can also be used. Crystallization yield 73.6 mg (50.9%). The solid fraction obtained by filtration contained the salt of (lSJ2JR)-l-(6-bromo-2-memoxyquinomi-3-yl)-4-dimemylarnino-2-(l- naphthyl)-l-phenyl-butan-2-ol lb and (i?)-(-)-l-(2-phenyl)-l53-propanediol-2,2-dimethyl hydrogen phosphate Illr with the chiral purity of 99.7%.
After the filtration the mother liquor was evaporated with the use of a vacuum evaporator and the obtained solid matter was re-dried in a vacuum drier at 40°C for 16 hours. The evaporation of the mother liquor provided 70.9 mg (49.1%) of solid matter representing the diastereoisomeric salt la with (i-)-(-)-l-(2-phenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate Illr with the chiral purity of 96.6%.
Example 5
Isolation of the salt of bedaquiline la with (5)-(+)-l-(2-phenyl)-l,3-propanediol-252-dimethyl hydrogen phosphate (Ills) from the I-rac racemic mixture in isopropyl alcohol
100 mg (1.80-10"4 mol) of the I-rac racemic mixture was dissolved in 13 ml of anhydrous isopropyl alcohol under reflux. 44.5 mg (1.80-10"4 mol) of (S (+)-l-(2-phenyl)-l,3- propanediol-2,2-dimethyI hydrogen phosphate Ills (98 %) (CAS RN: 98674-81-8) was dissolved in 2.2 ml of isopropyl alcohol and this solution was added to the I-rac solution and left to be stirred under reflux for 10 minutes. After cooling of the solution to the room temperature with continuous stirring, solid matter separated, which was filtered and dried in a vacuum drier at 40°C for 16 hours. Inoculation of the solution with prepared crystallization
inocula can also be used. Crystallization yield 72.1 mg (49.5%). The solid fraction obtained by filtration contained the salt of bedaquiline la with (<S)-(+)-l-(2-phenyl)-l}3-propanediol-2,2- dimethyl hydrogen phosphate Ills (with the chiral purity of 99.6% (HPLC purity 98%)). Example 6
Isolation of the salt of bedaquiline la with (i-)-(+)-l-(2-chlorophenyl)-l,3-propanediol-2,2- dimethyl hydrogen phosphate (VIr) from isopropyl alcohol
100 mg
(1.80-10"4 mol) of the I-rac racemic mixture was dissolved in 13 ml of isopropyl alcohol under reflux. 48.3 mg (1.80-10"4 mol) of (£)-(+)- l-(2-cMorophenyl)-l, 3 -propanediol-2 ,2- dimethyl hydrogen phosphate (CAS RN: 98674-87-4) VIr (97%) was dissolved in 2.2 ml of isopropyl alcohol and this solution was added to the I-rac solution and left to be stirred under reflux conditions for 10 minutes. After cooling of the solution to the room temperature with continuous stirring, solid matter separated, which was filtered and dried in a vacuum drier at 40°C for 16 hours. Inoculation of the solution with prepared crystallization inocula can also be used. Crystallization yield 63.8 mg (43%). The solid fraction obtained by filtration contained the salt of bedaquiline la with (i?)-(+)-l-(2-chlorophenyl)-l53-propanediol-2,2-dimethyl hydrogen phosphate VIr with the chiral purity of 99.2%. Example 7
Isolation of the salt of bedaquiline la with (i?)-(+)-l-(2-methoxyphenyl)-l,3-propanediol-2}2- dimethyl hydrogen phosphate Vr from the I-rac racemic mixture in isopropyl alcohol
100 mg (1.80-10"4 mol) of the I-rac racemic mixture was dissolved in 13 ml of isopropyl alcohol under reflux. 47.5 mg (1.80-10"4 mol) of ( )-(+)- l-(2-methoxyphenyl)- 1,3- propanediol-2,2-dimethyI hydrogen phosphate (CAS RN: 98674-82-9) Vr (97%) was dissolved in 2.2 ml of isopropyl alcohol and this solution was added to the I-rac solution and left to be stirred under reflux for 10 minutes. After cooling of the solution to the room temperature with continuous stirring, solid matter separated, which was filtered and dried in a vacuum drier at 40°C for 16 hours. Inoculation of the solution with prepared crystallization inocula can also be used. Crystallization yield 72 mg (49%). The solid fraction obtained by filtration contained the salt of bedaquiline la with (i-)-(+)-2-hydroxy-4-(2-methoxyphenyl)- SjS-dimethyl-l^^-dioxaphosphane 2-oxide Vr with the chiral purity of 99.8%.
Example 8
Isolation of the salt of bedaquiline la with (i?)-(H-)-l-(2-methoxyphenyl)-l,3-propanediol-252- dimethyl hydrogen phosphate Vr from the I-rac and Il-rac mixture of isomers (11:2) in isopropyl alcohol
100 mg (1.80-10"4 mol) of the mixture of the I-rac and Il-rac (11:2) mixture of isomers was dissolved in 13 ml of isopropyl alcohol under reflux. 47.5 mg (1.80-10"4 mol) of (i?)-(+)-l-(2- memoxyphenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate Vr (97 %) was dissolved in 2.2 ml of isopropyl alcohol and this solution was added to the solution of the mixture of the stereoisomers and was left to be stirred under reflux for 10 minutes. After cooling of the solution to the room temperature with continuous stirring, solid matter separated, which was filtered and dried in a vacuum drier at 40°C for 16 hours. Inoculation of the solution with prepared crystallization inocula can also be used. Crystallization yield 59.3 mg (40.2%; 95% calculated to bedaquiline only). The solid fraction obtained by filtration contained the salt of bedaquiline la with (i?)-(+)-2-hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-l,3,2- dioxaphosphane 2-oxide Vr with the chiral purity of 99.7%.
Example 9
Isolation of the free base of bedaquiline la.
Isolation of the free base of bedaquiline from the respective salt was carried out in accordance with the procedure described in a patent (WO 2006/125769).
Claims
1. A method of performing isolation and purification of bedaquiline (la) from a mixture of stereoisomers of 6-bromo-2-memoxy-quinolin-3-yl)-4-dimethylamino-2-(l-naphthyl)-l- phenyl-butan-2-ol identified as I-rac, being a mixture of the stereoisomers of formulae la, lb, and II-rac, being a mixture of the stereoisomers of formulae Ila, lib, with any ratio of individual constituents of the mixture, characterized in that said mixture is dissolved together with at least one derivative of 1,3 -propanediol hydrogen phosphate of formula IV
la lb Ila lib
I-rac = Ia:Ib II-rac = Ha.IIb
(IV) wherein Rl5 R2i and R3 independently stand for hydrogen, a halogen, Q-Ce alkyl, aryl, naphthyl, phenyl, and preferably a halogenated phenyl or phenyl substituted in any way, and the resulting salt is crystallized.
2. The method according to claim 1, characterized in that the isolation from the mixture of (1R,2S)- (1S,2R)- (1S,2S)- (1R.2R) of formulae la, lb, Ila, lib; I-rac with admixed II- rac is accomplished through crystallization of a salt of (£)-(+)- l-(2-phenyl)- 1,3- propanediol-2,2-dimethyl hydrogen phosphate Ills.
Ills
3. The method according to claim 1, characterized in that the isolation from the mixture of (1R,2S)- (1S,2R)- (1S,2S> (1R,2R) (la, lb, Ha, lib; I-rac with admixed II-rac) is accomplished through crystallization of a salt of (-¾)-(+)-l-(2-methoxyphenyl)-l,3- propanediol-2,2- sphate Vr.
Vr
4. The method according to claim 1, characterized in that the isolation from the mixture of (1R,2S)- (1S,2R)- (1S,2S> (1R,2R) (la, lb, Ila, lib) is accomplished through crystallization of a salt of (i?)-(+)- l-(2-chlorophenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate VIr
VIr
5. The method according to claim 1, characterized in that the isolation is accomplished from a mixture of (la, lb) (1R,2S)- and (lS,2R)-(6-bromo-2-methoxy-quinolin-3-yl)-4- dimethylamino-2-(l -naphthyl)- 1 -phenyl-butan-2-ol.
6. The method according to claim 5, characterized in that a salt with (R)-(-)-l-(2-phenyi)- l,3-propanediol-2,2-dimethyl hydrogen phosphate Illr is crystallized from the mixture (la, lb) of (1R,2S and (1S,2R .
III/·
7. The method according to claim 5, characterized in that a salt with (S)-(+)-l-(2-phenyl)- l,3-propanediol-2,2-dimethyl hydrogen phosphate Ills is crystallized from the mixture (la, lb) of (1R,2S> and (1S,2R .
8. The method according to claim 2, characterized in that a salt with (R)-(+)-l-(2- chlorophenyl)-l,3-propanedioi-2,2-dimethyl hydrogen phosphate VIr is crystallized from the mixture (la, lb) of (1R.2S)- and (1S.2R)-.
9. The method according to claim 2, characterized in that a salt with (S)-(-)-l-(2- chlorophenyl)-l,3-propanediol-2J2-dimethyl hydrogen phosphate Vis is crystallized from the mixture (la, lb) R,2S)- and (1S,2R)-.
Vis
10. The method according to claim 2, characterized in that a salt with (J?)-(+)-l-(2- methoxyphenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate Vr is crystallized from the mixture (la, lb) of (1R,2S and (1S,2R)-.
11. The method according to claim 2, characterized in that a salt with (5)-(-)-1-(2- methoxyphenyl)-l,3-propanediol-2,2-dimethyl hydrogen phosphate Vs is crystallized from the mixture (la, lb) of (1RS2S)- and (1S,2R)-.
Vs
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| KR102303635B1 (en) * | 2020-07-01 | 2021-09-17 | 동아에스티 주식회사 | PROCESS FOR PREPARING (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol AND PHARMACEUTICALLY ACCEPTABLE SALT |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1227085A1 (en) * | 1999-10-22 | 2002-07-31 | Takeda Chemical Industries, Ltd. | Process for producing optically active naphthalene derivative and optical resolver therefor |
| WO2004011436A1 (en) | 2002-07-25 | 2004-02-05 | Janssen Pharmaceutica N.V. | Quinoline derivatives and their use as mycobacterial inhibitors |
| WO2006125769A1 (en) | 2005-05-25 | 2006-11-30 | Janssen Pharmaceutica N.V. | Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol |
-
2015
- 2015-01-21 CZ CZ2015-35A patent/CZ201535A3/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1227085A1 (en) * | 1999-10-22 | 2002-07-31 | Takeda Chemical Industries, Ltd. | Process for producing optically active naphthalene derivative and optical resolver therefor |
| WO2004011436A1 (en) | 2002-07-25 | 2004-02-05 | Janssen Pharmaceutica N.V. | Quinoline derivatives and their use as mycobacterial inhibitors |
| WO2006125769A1 (en) | 2005-05-25 | 2006-11-30 | Janssen Pharmaceutica N.V. | Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol |
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| KR102303635B1 (en) * | 2020-07-01 | 2021-09-17 | 동아에스티 주식회사 | PROCESS FOR PREPARING (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol AND PHARMACEUTICALLY ACCEPTABLE SALT |
| CN114085185A (en) * | 2020-07-01 | 2022-02-25 | 东亚St 株式会社 | Process for preparing bedaquiline and pharmaceutically acceptable salts thereof |
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