WO2004063175A1 - A novel and an improved process for the preparation of (s)-4-(4-aminobenzyl)-2- oxazolidinone - Google Patents
A novel and an improved process for the preparation of (s)-4-(4-aminobenzyl)-2- oxazolidinone Download PDFInfo
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- WO2004063175A1 WO2004063175A1 PCT/IN2003/000341 IN0300341W WO2004063175A1 WO 2004063175 A1 WO2004063175 A1 WO 2004063175A1 IN 0300341 W IN0300341 W IN 0300341W WO 2004063175 A1 WO2004063175 A1 WO 2004063175A1
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- WIPO (PCT)
- Prior art keywords
- formula
- improved process
- oxazolidinone
- preparation
- methanol
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- WNAVSKJKDPLWBD-VIFPVBQESA-N (4s)-4-[(4-aminophenyl)methyl]-1,3-oxazolidin-2-one Chemical compound C1=CC(N)=CC=C1C[C@@H]1NC(=O)OC1 WNAVSKJKDPLWBD-VIFPVBQESA-N 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- PCLGMKWXPXAGEO-QMMMGPOBSA-N (2s)-2-amino-3-(4-nitrophenyl)propan-1-ol Chemical compound OC[C@@H](N)CC1=CC=C([N+]([O-])=O)C=C1 PCLGMKWXPXAGEO-QMMMGPOBSA-N 0.000 claims abstract description 12
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims abstract description 11
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 5
- 238000007796 conventional method Methods 0.000 claims abstract description 3
- 150000002828 nitro derivatives Chemical class 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 98
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 7
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 7
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- QLVWOKQMDLQXNN-UHFFFAOYSA-N dibutyl carbonate Chemical compound CCCCOC(=O)OCCCC QLVWOKQMDLQXNN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- JMPVESVJOFYWTB-UHFFFAOYSA-N dipropan-2-yl carbonate Chemical compound CC(C)OC(=O)OC(C)C JMPVESVJOFYWTB-UHFFFAOYSA-N 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims 1
- UTAZCRNOSWWEFR-ZDUSSCGKSA-N zolmitriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1C[C@H]1COC(=O)N1 UTAZCRNOSWWEFR-ZDUSSCGKSA-N 0.000 abstract description 5
- 229960001360 zolmitriptan Drugs 0.000 abstract description 5
- 208000019695 Migraine disease Diseases 0.000 abstract description 3
- 206010027599 migraine Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- GMTRSZXBNADBMK-VIFPVBQESA-N (2s)-2-amino-3-(4-aminophenyl)propan-1-ol Chemical compound OC[C@@H](N)CC1=CC=C(N)C=C1 GMTRSZXBNADBMK-VIFPVBQESA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 238000001816 cooling Methods 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- MHCRLDZZHOVFEE-UHFFFAOYSA-N 4-(4-aminophenyl)morpholin-3-one Chemical compound C1=CC(N)=CC=C1N1C(=O)COCC1 MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 0 *CCc1ccc(CC(CO)N)cc1 Chemical compound *CCc1ccc(CC(CO)N)cc1 0.000 description 4
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 4
- -1 Aminobenzyl Chemical group 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- GTVVZTAFGPQSPC-QMMMGPOBSA-N (2s)-2-azaniumyl-3-(4-nitrophenyl)propanoate Chemical compound OC(=O)[C@@H](N)CC1=CC=C([N+]([O-])=O)C=C1 GTVVZTAFGPQSPC-QMMMGPOBSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- KMJYOSPMGJPJEX-ZETCQYMHSA-N (2s)-2-(4-nitroanilino)propan-1-ol Chemical compound OC[C@H](C)NC1=CC=C([N+]([O-])=O)C=C1 KMJYOSPMGJPJEX-ZETCQYMHSA-N 0.000 description 1
- VSMANSLTTPNSMB-UHFFFAOYSA-N 3-(4-nitrophenyl)propan-1-ol Chemical compound OCCCC1=CC=C([N+]([O-])=O)C=C1 VSMANSLTTPNSMB-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- GMTRSZXBNADBMK-UHFFFAOYSA-N NC(Cc(cc1)ccc1N)CO Chemical compound NC(Cc(cc1)ccc1N)CO GMTRSZXBNADBMK-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WOMSTXBCVBQGKV-UHFFFAOYSA-N methanol;palladium Chemical compound [Pd].OC WOMSTXBCVBQGKV-UHFFFAOYSA-N 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
Definitions
- the present invention relates to an improved process for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone.
- (S)-4-(4-aminobenzyl)-2- oxazolidinone prepared* by the process of the present invention has the formula I given below and is useful for the preparation of zolmitriptan .
- Zolmitriptan is an important drug for the treatment of migraine.
- the process involves preparation of the above said compound of the formula I using novel intermediate of the formula II
- the process for the preparation of compound of formula (I) comprises (i) esterification of (S)-4-nitro-phenylalanine to give (S)-methyl-4-nitro phenyl alanate of the formula (III).
- step No.3 Yield reported in the step No.3 is only 41%. 2. Process involves use of phosgene which is dangerous and not preferable for using the process on a commercial scale. 3. Overall yield from step (1) to step (4) is only 17%.
- the second route disclosed in [WO 97/06162, WO 97/06163] which comprises of following steps:
- the main objective of the present invention is to provide an improved process for the preparation of (S)-4-(4-aminobenzyl)-2- oxazolidinone (I) which is inexpensive, scalable on a commercial scale , high yielding (40% overall yield) and safe.
- According to another objective of the present invention is to provide an improved process for the preparation of oxazolidinone of formula (I) by replacing the highly toxic phosgene with simple non-toxic reagents like dialkyl carbonates in the cyclization step thereby making the process safe and user friendly .
- Another objective of the present invention is to provide an improved process for the preparation of the oxazolidinone of the formula (I) by avoiding an additional step involving formation of a carbamate in the synthesis thereby reducing the number of steps and improving the overall yields.
- the ring formation step can be carried out in the presence of an amino group present on benzene ring of compound of the formula (II).
- dialkyl carbonates used in the ring formation step gave better yields than the phosgene method (30-35% higher overall yield).
- the present invention provides an improved process for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone of the formula (I)
- the 4-nitro-(S)-phenylalaninol of formula (IV) in the step (i) may be prepared by following the method described in the US patent No. 5466699.
- 4-nitro-(S)-phenylalaninol of formula (IV) may be prepared as follows:
- the metal catalyst used in step (ii) may be Raney nickel, Palladium/carbon, Platinum/carbon, preferably Raney nickel or 5% palladium on carbon.
- the amount of catalyst employed may range from 5% to 20% by weight.
- the reduction step may also be carried out by using metal/acid eg. SnC /HCI, Fe/HCI and the like.
- the alchoholic solvent used may be selected from methanol, ethanol, isopropanol and the like.
- the solvent used in step (ii) may be selected from methanol, ethanol, isopropanol, etc., preferably methanol.
- the hydrogen pressure used in case of catalytic hydrogenation may be in the range of 20-80 psi preferably in the range of 40-60 psi.
- the temperature of the hydrogenation may be preferably in the range of 30-40°C.
- the dialkyl carbonates used in step (iv) may be selected from dimethyl carbonate, diethylcarbonate, diisopropyl carbonate, dibutyl carbonate, preferably dimethyl or diethylcarbonate.
- the temperature of the reaction in cyclization step of (iv) may be preferably in the range of 90-130°C.
- the solvent used in recrystallization step (vi) may be selected from methanol, ethanol or isopropanol.
- Example 1 The details of the invention are given in the Examples given below which are provided for illustration only and therefore these examples should not be construed to limit the scope of the invention.
- Example 1 The details of the invention are given in the Examples given below which are provided for illustration only and therefore these examples should not be construed to limit the scope of the invention.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention disclosed in this application relates to an improved process for the preparation of the oxazolidinone of formula (I) It comprises (i) Preparing the 4-nitro-(S)-phenylalaninol of formula (IV) by conventional methods. (ii) Reducing the nitro compound of formula (IV), (iii) Reacting the resulting novel compound of the formula (II) with dialkyl carbonate at a temperature in the range of 80-200 °C. to produce the compound of the formula I. The compound of the formula I is useful for the preparation of zolmitriptan which is an important drug for the treatment of migraine.
Description
NOVEL AND AN IMPROVED PROCESS FOR THE PREPARATION OF (S)- 4-(4-AMINOBENZYL)-2- OXAZOLIDINONE
INTRODUCTION
The present invention relates to an improved process for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone. (S)-4-(4-aminobenzyl)-2- oxazolidinone prepared* by the process of the present invention has the formula I given below and is useful for the preparation of zolmitriptan .
O
H II
Zolmitriptan is an important drug for the treatment of migraine. The process involves preparation of the above said compound of the formula I using novel intermediate of the formula II
BACKGROUND OF INVENTION
In the literature only two processes are available to prepare (S)-4- (4-aminobenzyl)-2-oxazolidinone of the formula (I).
In the first route disclosed in WO 9118871 (corresponding to US patent No 5466699), the process for the preparation of compound of formula (I) comprises
(i) esterification of (S)-4-nitro-phenylalanine to give (S)-methyl-4-nitro phenyl alanate of the formula (III).
(2) Reducing the compound of the formula (III) with sodiumborohydride to give (S)-4-nitrophenylalanilol of the formula (IV).
(3) Cyclising the compound of the formula (IV) using phosgene to give (S)-4-(4-nitrobenzyl)l,3-oxazolidinone of the formula (V).
(4) Hydrogenating the compound of the formula (V) with 5% Pd-C to give (S)-4- (Aminobenzyl)-l,3-oxazolidinone of the formula (I).
The main draw backs of the process are :
1. Yield reported in the step No.3 is only 41%. 2. Process involves use of phosgene which is dangerous and not preferable for using the process on a commercial scale. 3. Overall yield from step (1) to step (4) is only 17%.
The second route disclosed in [WO 97/06162, WO 97/06163] which comprises of following steps:
a) Forming a carbamate from methyl-4-nitro-(L)-phenylalanate HCI represented by the formula (III) by the reaction of sodium carbonate (or) sodium hydrogen carbonate and n-butylchloroformate to give methyl (S)-N-butoxycarbonyl-4-nitrophenyl alanate of the formula (VI).
c) Reduction of the methyl ester group (- CO2CH3) in the compound of the formula (VII) to give (S)-N-butoxycarbonyl-4-aminophenylaIaninol of the formula (VIII).
d) Ring closure of the compound of the formula (VIII) with 30% sodium methoxide in methanol to give (S)-4-(Aminobenzyl)-l,3-oxazolidinone of the formula (I).
This process involves relatively more expensive reagent butyl chloro formate in step (a) and step (d) needs extremely dry conditions and involves use of anhydrous sodium methoxide. These critical process parameters are very difficult to maintain consistently in a process plant, more so while taking scale up on commercial batches. Yields are not mentioned in the patent for any of the stages mentioned. However, we have found that experimentally only 20-25% overall yields are realized.
Considering the importance gained by Zolmitriptan for the treatment of migraine for which the compound of the formula I is an important intermediate there is a great need for developing a simple inexpensive and safe method for the commercial scale preparation of (S)-4-(4- aminobenzyl)-2-oxazolidinone of the formula I
Therefore the main objective of the present invention is to provide an improved process for the preparation of (S)-4-(4-aminobenzyl)-2- oxazolidinone (I) which is inexpensive, scalable on a commercial scale , high yielding (40% overall yield) and safe.
According to another objective of the present invention is to provide an improved process for the preparation of oxazolidinone of formula (I) by replacing the highly toxic phosgene with simple non-toxic reagents like dialkyl carbonates in the cyclization step thereby making the process safe and user friendly .
Yet another objective of the present invention is to provide an improved process for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone of the formula (I) starting from (S)-4-Nitrophenyl-alaninol of the formula (IV).
Still another objective of the present invention is to provide an improved process for the preparation of oxazolidinone of the formula (I) by carrying out the aromatic nitro group reduction in the early part of the synthesis there by producing a novel intermediate .
Another objective of the present invention is to provide an improved process for the preparation of the oxazolidinone of the formula (I) by avoiding an additional step involving formation of a carbamate in the synthesis thereby reducing the number of steps and improving the overall yields.
SUMMARY OF INVENTION
Keeping in view of the difficulties in commercialization of the processes disclosed in the above mentioned prior art patents, we aimed our research work to develop a simple and convenient process for the preparation of the oxazolidinone of the formula (I) which can be utilized for the preparation of zolmitriptan of the formula (A).
In our sustained research to develop a simple process for the preparation of the oxazolidinone of the formula (I), we observed that a promising approach for developing such a process would be to.
a) Avoid the usage of phosgene in the ring formation step.
b) Reduce the nitro group present in the compound of the formula (IV) with appropriate reducing agent before the cyclisation step.
c) Use of dialkylcarbonates like dimethyl carbonate, diethyl carbonate in ring formation step.
Accordingly we focused our research on the above mentioned directions. Following the above directions we are successful to develop an improved process for the preparation of oxazolidinone of the formula (I).
Accordingly, we observed that the ring formation step can be carried out in the presence of an amino group present on benzene ring of compound of the formula (II).
We also found further that dialkyl carbonates used in the ring formation step gave better yields than the phosgene method (30-35% higher overall yield).
Accordingly, the present invention provides an improved process for the preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone of the formula (I)
O
H ||
O H II
We have described and claimed the novel intermediate of the formula II in a separate application which is being filed simultaneously with this application
The 4-nitro-(S)-phenylalaninol of formula (IV) in the step (i) may be prepared by following the method described in the US patent No. 5466699.
For example 4-nitro-(S)-phenylalaninol of formula (IV) may be prepared as follows:
Esterification of (S)- 4-nitro phenylalanine with methanol, and thionyl chloride at -10°C yields (S)- methyl-4-nitro phenylalanate hydrochloride of the formula (III).
Compound of the formula (III) on reduction with sodium borohydride in aqueous ethanol medium yields compound of the formula (IV).
The metal catalyst used in step (ii) may be Raney nickel, Palladium/carbon, Platinum/carbon, preferably Raney nickel or 5% palladium on carbon. The amount of catalyst employed may range from 5% to 20% by weight. The reduction step may also be carried out by using metal/acid eg. SnC /HCI, Fe/HCI and the like.
The alchoholic solvent used may be selected from methanol, ethanol, isopropanol and the like.
The solvent used in step (ii) may be selected from methanol, ethanol, isopropanol, etc., preferably methanol. The hydrogen pressure used in case of catalytic hydrogenation may be in the range of 20-80 psi preferably in the range of 40-60 psi. The temperature of the hydrogenation may be preferably in the range of 30-40°C.
The dialkyl carbonates used in step (iv) may be selected from dimethyl carbonate, diethylcarbonate, diisopropyl carbonate, dibutyl carbonate, preferably dimethyl or diethylcarbonate. The temperature of the reaction in cyclization step of (iv) may be preferably in the range of 90-130°C.
The solvent used in recrystallization step (vi) may be selected from methanol, ethanol or isopropanol.
A particularly preferred reaction scheme for the preparation of the compound of the formula (I) is shown below :
"γNH2 (i) Hydrogen, 5%Pd-C
O2N CH2OH Methanol, RT
(I)
The details of the invention are given in the Examples given below which are provided for illustration only and therefore these examples should not be construed to limit the scope of the invention.
Example 1:
The preparation of S-4-(4-Aminobenzyl)-2-oxazolidinone
A) The preparation of (S)-2-amino-3-(4-aminophenyl)propanol
(i) Hydrogen, 5%Pd-C Methanol, RT
CgHi2N2O3 C9H14N2O
M.W : 196.0 M.W : 166.0
Raw materials Qty
1. (S)-2-Amino-3-(4-nitro phenyl) propanol 10.0 Kg
2. Methanol 111.0 Kg
3. 5% Palladium carbon (50% water wet) 2.0 Kg
4. Ethyl acetate 24.0 Kg
5. n-Hexane 20.0 Kg
6. Hydrogen as required
Procedure
Charge to the reactor the methanolic solution of (S)-2-Amino-3-(4-nitro phenyl)-propanol, and 5% palladium carbon catalyst and hydrogenate at about 60 psi of hydrogen at room temperature. On completion, filter off the catalyst through filter aid and wash with methanol. The methanol solution of novel (S)-2-Amino-3-(4-aminophenyl) propanol of the formula (II) is completely distilled under vacuum.
Charge the mixture of ethyl acetate and n-Hexane to the residue. After cooling the solution to 10°C for about 2 hours, filter and wash the filtered product with n-hexane and dry it about 50°C in vacuum (7.6 Kg, 89.5%; mp 108-112°C)
HPLC purity - 99%.
Analysis : C9H14N2O; molecular weight : 166.0
IR spectrum - KBr disc
Absence of - NO2 NH2 at 3307 and 3368 cnrf1
UV spectrum - Methanol λmax at 238.75 nm λmin at 293.15nm
XH NMR (DMSO - d6) (ppm) 2.15 - 2.30 and 2.40-2.55 (m,2H, Ph-Cjhh)
2.60-2.85 (m,lH, CH-NH2)
3.05-3.20 and 3.20-3.40 (m,2H, CH2- OH)
6.40-6.55 (d, 2H, Ar-protons)
6.75-6.95 (d, 2H, Ar-protons)
40.0 (Ar.CH2 )
54.6 (-CH - NH2)
65.6 (-CH2 - OH) (Ar. Carbon)
B) The preparation of (S)-4- (4-aminobenzyl)-2-oxazolidinone.
O
C9H14N2O C-10H-12N2O2 M.W : 166.0 M.W : 192.0
Raw materials Qty
1. (S)-2-Amino-3-(4-amino phenyl) propanol 7.6Kg
2. Diethyl carbonate 13.5 Kg
3. Potassium carbonate , 0.633 Kg
4. Methanol 35.0 Kg
5. isopropanol 9.5Kg
Procedure
Charge into reactor (S)-2-Amino-3-(4-amino phenyl)-propanol obtained by the process explained in step(A) , diethyl carbonate and potassium carbonate at 135°C. Distill off ethanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off the filtered methanol completely under vacuum and charge isopropanol to the residue. Filter through filter aid and wash the product ((S)-4- (4- aminobenzyl)-2-oxazolidinone) with isopropanol. Dry at 50°C in vacuum (6.85 Kg, 76.7%, mp 95-100°C).
Analysis : C10H12N2O2, molecular weight : 192.0
IR spectrum : KBr, Lactone : 1759 cm"1
*HNMR and 13CNMR were consistent with the proposed structure.
Example 2:
O2N CH2OH
C9H12N2θ3 C9H14N2O
M.W : 196.0 M.W : 166.0
A) The preparation of (S)-2-amino-3- (4-aminophenyl) propanol.
Raw materials Qty
1. (S)-2-Amino ■3-(4-nitro phenyl) propanol lO.OKg
2. Iron filings 30.6 Kg
3. 95% Ethanol 35.0 Kg
4. Cone. Hydrochloric acid 0.610 Kg
5. Ethyl acetate 20.0 Kg
6. n-Hexane 16.0 Kg
7. DM water 10 Kg
Procedure
Charge into reactor (S)-2-Amino-3-(4-nitrophenyl)-propanol, 95% ethanol, iron filings, DM water and cone. Hydrochloric acid at room temperature. Reflux the reaction mass for three hours. After cooling the reaction mass to room temperature filter off iron through filter aid and wash thoroughly with 95% ethanol. Distill off the ethanol solution of (S)-2-amino-3- 4(aminophenyl)propanol completely under vacuum.
Charge the mixture of ethyl acetate and n-Hexane to the residue. After cooling the solution to 10°C for about 2 hours, filter and wash the filtered product with n-Hexane and dry it about 50°C in vacuum (6.2 Kg, 73.0%, mp : 107-111°C) HPLC purity : 98.7%
Analysis : C9H14N2O, molecular weight : 166.0
IR , *HNMR and 13CNMR were consistent with the proposed structure.
B) The preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone.
Dimethyl carbonate
Potassium carbonate
C9Hι4N2O C10H12N2O2 M.W : 166.0 M.W : 192.0
Raw materials Qty
1. (S)-2-Amino-3-(4-aminophenyl) propanol 6.2 Kg
2. Dimethyl carbonate 8.4 Kg
3. Potassium carbonate 0.520Kg
4. Methanol 30.0 Kg
5. Isopropanol 7.5 Kg
Procedure
Charge into reactor (S)-2-Amino-3-(4-aminophenyl) propanol prepared by the process explained in step (A) , dimethyl carbonate and potassium carbonate at 115-120°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product [(S)-4- (4-aminobenzyl)-2- oxazolldinone] with isopropanol. Dry at 50°C In vacuum (5.5 Kg, 75.0% , mp 95-100°C)
Analysis : C10H12N2O2, molecular weight : 192.0
IR , ^N R and 13CNMR were consistent with the proposed structure.
Example 3:
A) The preparation of (S)-2-amino-3- (4-aminophenyl) propanol.
C9H12N2O3 C9H14N2O
M.W : 196.0 M.W : 166.0 Raw materials Qty
1. (S)-2-Amino-3-(4-amino phenyl) propanol - lO.OKg
2. Stannous chloride dihydrate 61.0 Kg
3. Cone. Hydrochloric acid 178.0 Kg
4. 50% sodium hydroxide solution 250 Kg
5. Ethyl acetate 20.0 Kg
6. n-Hexane 15.0 Kg
7. DM water 500 L
Procedure
Charge into reactor cone. Hydrochloric acid and stannous chloride dihydrate at room temperature. Cool to 0°C. Add (S)-2-amino-3-(4-nitrophenyl) propanol lot wise slowly at 0-5°C during two hours. Bring reaction mass to room temperature and maintain for two hours at 25-35°C. Charge 200 L DM water to the reactor and adjust pH to 12-13 with 50% sodium hydroxide solution. Filter the separated mass through filter aid. Suspend the filtered solid into reactor and charge ethyl acetate and extract for 30 minutes. Filter again through filter aid and water wash ethyl acetate layer with DM water till pH of last washing is neutral. Concentrate ethyl acetate solution of (S)-2-Amino-3-(4-aminophenyl)-propanol, to a residual quantity of 15-20 Kgs. Cool to room temperature and n-Hexane to the residue. After cooling
the solution to 10°C for about 2 hours, filter and wash the filtered product with n-Hexane and dry it about 50°C in vacuum (5.1 Kg, 60.0%, mp : 108- 110°C) HPLC purity 99.1% Analysis : C9H14N2O, molecular weight : 166.0 IR , XHNMR and 13CNMR were consistent with the proposed structure.
B) The preparation of (S)-2-amino-3-(4-aminophenyl) propanol.
Dimethyl carbonate
Potassium carbonate
C9H14N2O C10H12N2O2 M.W : 166.0 M.W : 192.0
Raw materials Qty
1. (S)-2-Amino-3-(4-aminophenyl) propanol 5.1 Kg
2. Dimethyl carbonate 9.1 Kg
3. Potassium carbonate 0.42 Kg
4. Methanol 25.0 Kg
5. Isopropanol 6.5 Kg
Procedure
Charge into reactor (S)-2-Amino-3-(4-aminophenyl) propanol obtained by the process explained in step (A) , dimethyl carbonate and potassium carbonate at 135°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature, charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product with isopropanol. Dry at 50°C under vacuum (4.5 Kg, 76.0% , mp 95-100°C)
Analysis : C10H12N2O2, molecular weight : 192.0
IR , *HNMR and 13CNMR were consistent with the proposed structure.
Example 4
A) The preparation of (S)-2-amino-3- (4-aminophenyl) propanol.
Raney Nickel
O2N CH2OH Ethanol
C9H12N2O3 C9H14N2O M.W : 196.0 M.W : 166.0
Raw materials Qty
1. (S)-2-Amino-3-(4-nitrophenyl) propanol lO.OKg
2. Raney Nickel 0.650 Kg
3. Anhydrous ethanol 22.0 Kg
4. Ethyl acetate 24.0 Kg
5. n-Hexane 20.0 Kg
Procedure
Charge into reactor ethanolic solution of (S)-2-Amino-3-(4-aminophenyl) propanol and Raney nickel catalyst and hydrogenate at about 60 psi of hydrogen at room temperature. On completion, filter off catalyst through filter aid and wash with ethanol. The ethanol solution of (S)-2-Amino-3-(4- aminophenyl) propanol of the formula (II) is completely distilled under vacuum. Charge mixture of ethyl acetate and n-hexane to the residue. After cooling the solution to 10°C for about 2 hours, filter and wash the filtered product with n-Hexane and dry it about 50°C in vacuum (7.5 Kg, 88.3%, mp : 107-111°C)
Analysis : C9H14N2O, molecular weight : 166.0
IR , *HNMR and 13CNMR were consistent with the proposed structure.
B) The preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone
C9H14N2O C10H12N2O2 . M.W : 166.0 M.W : 192.0
Raw materials Qty
1. (S)-2-Amino-3-(4-aminophenyl) propanol 7.5 Kg 2. Dimethyl carbonate 13.3 Kg
3. Potassium carbonate 0.62 Kg
4. Methanol 35.0 Kg
5. Isopropanol 9.4 Kg
Procedure
Charge into reactor (S)-2-Amino-3-(4-aminophenyl) propanol obtained by the process described in step (A), dimethyl carbonate and potassium carbonate at 135°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product[(S)-4-(4-aminobenzyl)-2- oxazolidinone.] with isopropanol. Dry at 50°C under vacuum (6.75 Kg, 76.7%, mp 95-100°C)
Analysis : C10H12N2O2, molecular weight : 192.0
IR , *HNMR and 13CNMR were consistent with the proposed structure.
Advantages of the process of the present invention
• The process is more efficient in terms of yields. 40% overall yields are realized for the production of compound of the formula (I) starting from compound of the formula (III) when compared to 17% reported in literature.
• The process does not involve use of toxic reagents like phosgene which is all the more difficult when operating on a commercial scale.
• The process does not involve additional steps as preparation of a carbamate as is the case with the process employing butyl chloroformate.
• The process also avoids employing extremely dry conditions required while handling sodium methoxide as in the butyl chloroformate process
• The process results in providing a novel intermediate of the formula II
• The process is commercially viable.
Claims
1. An improved process for the preparation of (S)-4-(4-aminobenzyl)-2- oxazolidinone of the formula 1 .
O
(ii)Reducing the nitro compound of formula (IV) by hydrogenation in the presence of a metal catalyst in alcoholic solvents under pressure at a temperature in the range of 25-80°C, to produce a novel intermediate of the formula (II).
(iii) Isolating the reduced product of formula (II) by filtration of catalyst and followed by distillation of solvent, (iv) Reacting the novel compound of the formula (II) with dialkyl carbonate at a temperature in the range of 80-200 °C. (v) Isolating the oxazolidinone of the formula (I) by distilling off dialkyl carbonate at a temperature below its boiling point.
O H II
(vi) Recrystallising the oxazolidinone of the formula (I) above from an alcoholic solvent.
2. An improved process as claimed in claim 1 wherein the 4-nitro-(S)- phenylalaninol of formula (IV) in the step (i) is prepared by following the method described in the US patent No 5466699
3. An improved process as claimed in claim 2 wherein the 4-nitro-(S)- phenylalaninol of formula (IV) in the step (i) is prepared by reduction of methyl-(S)-4-nitrophenylalanate hydrochloride of the formula (III) with
4. An improved process as claimed in claims 1 to 3 wherein the metal catalyst used in step (ii) is selected from Raney nickel, Palladium/carbon, Platinum/carbon, preferably Raney nickel or palladium on carbon.
5. An improved process as claimed in claims 1 to 4 wherein the amount of catalyst employed ranges from 5% to 20% by weight.
6. An improved process as claimed in claims 1 to 3 wherein the reduction step is carried out by using other metal/acid catalysts for example SnCI2/HCI, Fe/HCI and the like.
7. An improved process as claimed in claims 1 to 6 wherein the solvent used in step (ii) is selected from methanol, ethanol or isopropanol etc., preferably methanol.
8. An improved process as claimed in claims 1 to 7 wherein the hydrogen pressure used in case of catalytic hydrogenation ranges from 20-80 psi preferably in the range of 40-60 psi.
9. An improved process as claimed in claims 1 to 8 wherein the hydrogenation temperature used ranges preferably from 30-40°C.
10. An improved process as claimed in claims 1 to 9 wherein the dialkyl carbonates used in step (iv) is selected from dimethyl carbonate, diethyl carbonate, diisopropyl carbonate, dibutyl carbonate, preferably dimethyl or diethylcarbonate.
11 An improved process as claimed in claims 1 to 10 wherein the temperature of the reaction in cyclization step of (iv) ranges from 90- 130°C.
12. An improved process as claimed in claims 1 to 11 wherein the solvent used in recrystallization step (vi) is selected from methanol, ethanol or isopropanol.
13. An improved process for the preparation of (S)-4-(4-aminobenzyl)-2- oxazolidinone of the formula 1 as defined in claiml substantially as herein described with reference to the Examples .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003278593A AU2003278593A1 (en) | 2003-01-13 | 2003-10-21 | A novel and an improved process for the preparation of (s)-4-(4-aminobenzyl)-2- oxazolidinone |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN29/MAS/2003 | 2003-01-13 | ||
| IN29CH2003 | 2003-01-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004063175A1 true WO2004063175A1 (en) | 2004-07-29 |
Family
ID=32697213
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2003/000341 WO2004063175A1 (en) | 2003-01-13 | 2003-10-21 | A novel and an improved process for the preparation of (s)-4-(4-aminobenzyl)-2- oxazolidinone |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2004063175A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5466699A (en) * | 1990-06-07 | 1995-11-14 | Burroughs Wellcome Co. | Indolyl compounds for treating migraine |
-
2003
- 2003-10-21 WO PCT/IN2003/000341 patent/WO2004063175A1/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5466699A (en) * | 1990-06-07 | 1995-11-14 | Burroughs Wellcome Co. | Indolyl compounds for treating migraine |
Non-Patent Citations (1)
| Title |
|---|
| REBSTOCK M C ET AL: "Chloramphenicol (Chloromycetin). IV. Chemical Studies", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 71, 1949, pages 2458 - 2462, XP002268527, ISSN: 0002-7863 * |
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