WO2022219485A1 - A scalable process for the preparation of substantially pure glycine tert-butyl ester and its salt thereof - Google Patents
A scalable process for the preparation of substantially pure glycine tert-butyl ester and its salt thereof Download PDFInfo
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- WO2022219485A1 WO2022219485A1 PCT/IB2022/053352 IB2022053352W WO2022219485A1 WO 2022219485 A1 WO2022219485 A1 WO 2022219485A1 IB 2022053352 W IB2022053352 W IB 2022053352W WO 2022219485 A1 WO2022219485 A1 WO 2022219485A1
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- formula
- tert
- compound
- butyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 150000003839 salts Chemical class 0.000 title claims abstract description 14
- 238000010963 scalable process Methods 0.000 title description 3
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 10
- 125000001475 halogen functional group Chemical group 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- -1 n-hcptanc Natural products 0.000 claims description 4
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical group CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 0.000 claims description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Chemical group 0.000 claims description 3
- 229910052791 calcium Chemical group 0.000 claims description 3
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 claims description 2
- QYPDJIDQEZDFLS-UHFFFAOYSA-N tert-butyl 2-iodoacetate Chemical compound CC(C)(C)OC(=O)CI QYPDJIDQEZDFLS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 229940086542 triethylamine Drugs 0.000 claims description 2
- ZIXLDMFVRPABBX-UHFFFAOYSA-N alpha-methylcyclopentanone Natural products CC1CCCC1=O ZIXLDMFVRPABBX-UHFFFAOYSA-N 0.000 claims 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N phenyl propionaldehyde Natural products CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000746 purification Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- DEGPIRUPAKWDBU-UHFFFAOYSA-N isoindole-1,3-dione;sodium Chemical compound [Na].C1=CC=C2C(=O)NC(=O)C2=C1 DEGPIRUPAKWDBU-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 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 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- XFLQIRAKKLNXRQ-UUWRZZSWSA-N elobixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)NCC(O)=O)C=3C=CC=CC=3)C=C2S(=O)(=O)CC(CCCC)(CCCC)CN1C1=CC=CC=C1 XFLQIRAKKLNXRQ-UUWRZZSWSA-N 0.000 description 1
- 229950000820 elobixibat Drugs 0.000 description 1
- 108010007192 elobixibat Proteins 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- 229960004796 rosuvastatin calcium Drugs 0.000 description 1
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- UIYDKIPEEJMONH-QGZVFWFLSA-N tert-butyl (2r)-2-phenyl-2-(phenylmethoxycarbonylamino)acetate Chemical compound N([C@@H](C(=O)OC(C)(C)C)C=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 UIYDKIPEEJMONH-QGZVFWFLSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- RYVBINGWVJJDPU-UHFFFAOYSA-M tributyl(hexadecyl)phosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC RYVBINGWVJJDPU-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
Definitions
- the present invention relates to a scalable and efficient process for the preparation of substantially pureGlycine tert-butyl ester.
- the invention further relates to preparation of substantially pureGlycine tert-butyl esterand its salt of formula (I) using commercially available metal phthalimide in presence of inorganic base and solvent.
- Glycine tert-butyl ester [CAS No. 6456-74-2] is an important raw material in peptide synthesis.lt is also used widely in the preparation of various intermediates and APIs. For example, Glycine tert-butyl ester is used for a synthesis of Rosuvastatin tert-butyl glycinate salt to manufacture Rosuvastatin calcium and in preparation of (R)-2-benzyloxy carbonylamino-2-phenyl-acetic acid tert-butyl ester to prepare Elobixibat.
- the inventors of the present invention have developed a robust, cost-effective, and scalable process for preparation of substantially pureGlycine tert-butyl ester and its salt with purity more than96%.
- the invention provides an improved process of substantially pureGlycine tert- butyl ester and its saltof formula (I)where X is Cl, Br, I
- the present invention provides a cost-effective process by avoiding toxic, expensive reagents, catalysts, multiple operations(s) in an environment friendly and industrially scalable manner.
- the present invention provides a process for the preparation of substantially pure Glycine tert-butyl ester and its salts thereof formula (I) with or without involving purification.
- the present invention relates to a processfor the preparation of substantially pure Glycine tert-butyl ester and its salts (I)where aprocess comprises the steps: a) reacting a compound of formula (II) where M is Potassium or Calcium, with tert-butyl halo acetate of formula (III) to obtain compound of formula (IV) in presence of an inorganic base and solvent; b) reacting compound of formula (IV) with base in presence of chlorinated solvent; c) treating with acid.
- the present invention relates to a processfor the preparation of substantially pureGlycine tert-butyl ester and its salts (I) where a process comprises the steps: a) reacting a compound of formula (II) where M is Potassium or Calcium, with tert-butyl halo acetate of formula (III) to obtain compound of formula (IV) in presence of an inorganic base and solvent; b) optionally purifying in hydrocarbon solvent; c) reacting compound of formula (IV) with base in presence of chlorinatedsolvent; d) treating with acid; e) optionally purifying in ketonic solvent.
- the instant invention provides the preparation of substantially pureGlycine tert-butyl ester and its salts which involve only two steps, starting from commercially availablepotassium or sodiumphthalimide and tert-butyl halo acetate, thus the process is economically viable.
- solvent used herein refers to the single solvent or mixture of solvents.
- substantially pureGlycine tert-butyl ester and its salt of formula (I) is prepared by reacting potassium or sodium phthalimideof formula (II) and tert-butyl halo acetate of formula (III) in mild reaction conditions to obtain compound of formula (IV), which on further treatment with base resulted into desired substantially pureGlycine tert-butyl ester.
- the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 90%.
- the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 96%.
- the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 99%.
- the process for preparation of substantially pure Glycine tert-butyl ester and its salts does not involve purification step and generates less effluent, thus process is environment friendly and thereby industriallyscalable.
- the present invention provides a process for the preparation of substantially pureGlycine tert-butyl ester and its salt of formula (I) is illustrated in the following synthetic scheme.
- the present invention provides an improved process for preparation of compound (IV) by reacting commercially available reagents such as potassium or sodium phthalimide and tert-butyl halo acetate in presence of inorganic base and without use of costly catalyst.
- commercially available reagents such as potassium or sodium phthalimide and tert-butyl halo acetate
- tert-butyl halo acetate is selected from tert-butyl chloro acetate, tert-butyl bromoacetate and tert-butyl iodoacetate; more preferably tert-butyl chloroacetate.
- step (a) wherein the inorganic base in step (a) is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (CS2CO3), potassium carbonate (K2CO3), and sodium carbonate (Na 2 C0 3 ).
- solvent in step (a) is selected from N,N- dimethylformamide (DMF), toluene, eye lo hexane, 77-hcptanc, mo no-halo benzenes such as monochlorobenzene, dihalobenzenes such as dichlorobenzene, dialkyl (CfCi2) ethers, and the like; more preferably N,N-dimethylformamide.
- DMF N,N- dimethylformamide
- toluene eye lo hexane
- 77-hcptanc mo no-halo benzenes
- monochlorobenzene such as monochlorobenzene, dihalobenzenes such as dichlorobenzene, dialkyl (CfCi2) ethers, and the like
- CfCi2 dialkyl
- hydrocarbon solvent is selected from toluene, cyclohexane, 77-heptane, pentane and the like; more preferably 77-heptane.
- the base used in the preparation of compound (I) isselected from hydrazine hydrate, hydrazine mono hydrate, and triethyl amine; preferably hydrazine mono-hydrate.
- chlorinated solvent is selected from chloroform, dichloromethane, dichloroethane and the like.
- an acid is selected from hydrochloric acid in 1,4-dioxane, hydrochloric acid in hexane, hydrochloric acid in methanol, hydrochloric acid in toluene, hydrochloric acid in isopropyl alcohol; preferably in hydrochloric acid in 1,4- dioxane.
- aketonic solvent is selected from acetone, methyl ethyl ketone, acetophenone, cyclopentanone, 2-pentanone, preferablyacetone.
- a compound of formula (IV) was charged into n-heptane(3-5V) at 20°C to 30°C. The mixture was heated at 90°C to 100 °C for 2 hrsand cooled to 20°C to 30°C and stirred for 2 hrs. The solution was filtered, washed with n-hcptanc (IV), dried to obtain pure compound formula (IV; yield: 1.9-2.14 Kg, 85-95%; HPLC purity 99.5%).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a scalable and efficient process for the preparation of substantially pure Glycine tert-butyl ester. The invention further relates to preparation of substantially pure Glycine tert-butyl ester and its salt of formula (I) using commercially available metal phthalimide, inorganic base and solvent.
Description
“A SCALABLE PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE
GLYCINE TERT-BUTYL ESTER AND ITS SALT THEREOF”
RELATED APPLICATION
This application claims the benefit to Indian Provisional Application No. IN202121017102, filed on April 11, 2021, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to a scalable and efficient process for the preparation of substantially pureGlycine tert-butyl ester.The invention further relates to preparation of substantially pureGlycine tert-butyl esterand its salt of formula (I) using commercially available metal phthalimide in presence of inorganic base and solvent.
BACKGROUND OF THE INVENTION
Glycine tert-butyl ester[CAS No. 6456-74-2] is an important raw material in peptide synthesis.lt is also used widely in the preparation of various intermediates and APIs. For example, Glycine tert-butyl ester is used for a synthesis of Rosuvastatin tert-butyl glycinate salt to manufacture Rosuvastatin calcium and in preparation of (R)-2-benzyloxy carbonylamino-2-phenyl-acetic acid tert-butyl ester to prepare Elobixibat. It is essential to remove any impurities during preparation of Glycine tert-butyl ester to avoid further creation of additional impurities, or cascading impurities which may be difficult to remove in final APIs. Thus, preparationof substantially pureGlycine tert-butyl ester and its salts is extremely important.
Several publications such as CN 104263795; CN 103214383; KR 2012108225; e-EROS Encyclopedia of Reagents for Organic Synthesis, 2001, 1-2; Organic & Biomolecular Chemistry, 10 (30) 5787-5790; Bioorganic & Medicinal Chemistry, 22 (14) 4854-4858; Tetrahedron Letters, 53 (6), 641-645, 2012;Jr. Justus Liebigs Annalen der Chemise, Vol 660, 54-59, 1962, and the like disclosed the preparation of Glycine tert-butyl ester. The known
processes however, have one or the other disadvantages, for example:(i) use of toxicor expensive reagents such as pyridine, phosphorus oxychloride, perchloro acid, sulfuric acid, sodium azide, phenyl hydrazine; (ii) use of expensive catalysts such as triethyl benzyl ammonium chloride, hexadecyltributyl phosphonium bromide; (iii) more number of step; (iv) tedious and troublesome operations such as higher reaction temperature, extraction; distillation, purification; (v) low chemical purity. Thus, these processes are not an industrially scalable.
To overcome the limitations of the prior processes known in the art, the inventors of the present invention have developed a robust, cost-effective, and scalable process for preparation of substantially pureGlycine tert-butyl ester and its salt with purity more than96%.
SUMMARY OF THE INVENTION
In one aspect, the invention provides an improved process of substantially pureGlycine tert- butyl ester and its saltof formula (I)where X is Cl, Br, I
In another aspect, the present invention provides a cost-effective process by avoiding toxic, expensive reagents, catalysts, multiple operations(s) in an environment friendly and industrially scalable manner.
In another aspect, the present invention provides a process for the preparation of substantially pure Glycine tert-butyl ester and its salts thereof formula (I) with or without involving purification.
In another aspect, the present invention relates to a processfor the preparation of substantially pure Glycine tert-butyl ester and its salts (I)where aprocess comprises the steps:
a) reacting a compound of formula (II) where M is Potassium or Calcium, with tert-butyl halo acetate of formula (III) to obtain compound of formula (IV) in presence of an inorganic base and solvent;
b) reacting compound of formula (IV) with base in presence of chlorinated solvent; c) treating with acid.
In another aspect, the present invention relates to a processfor the preparation of substantially pureGlycine tert-butyl ester and its salts (I) where a process comprises the steps:
a) reacting a compound of formula (II) where M is Potassium or Calcium, with tert-butyl halo acetate of formula (III) to obtain compound of formula (IV) in presence of an inorganic base and solvent; b) optionally purifying in hydrocarbon solvent; c) reacting compound of formula (IV) with base in presence of chlorinatedsolvent; d) treating with acid; e) optionally purifying in ketonic solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is described more in details hereinafter. The invention is embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.
In one embodiment, the instant invention provides the preparation of substantially pureGlycine tert-butyl ester and its salts which involve only two steps, starting from
commercially availablepotassium or sodiumphthalimide and tert-butyl halo acetate, thus the process is economically viable.
The term solvent used herein, refers to the single solvent or mixture of solvents.
In another embodiment of the present invention, wherein substantially pureGlycine tert-butyl ester and its salt of formula (I) is prepared by reacting potassium or sodium phthalimideof formula (II) and tert-butyl halo acetate of formula (III) in mild reaction conditions to obtain compound of formula (IV), which on further treatment with base resulted into desired substantially pureGlycine tert-butyl ester.
In another embodiment of the present invention, wherein the preparation of compound of formula (IV) is carried out under self-exotherm, minimum volume of solvent and, isolated by quenching in water and avoiding distillation process. The resulting compound of formula (IV) is optionallypurified by simple crystallization in hydrocarbon solvent.
In one embodiment, the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 90%.
In one embodiment, the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 96%.
In one embodiment, the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 99%.
In another embodiment, the process for preparation of substantially pure Glycine tert-butyl ester and its salts does not involve purification step and generates less effluent, thus process is environment friendly and thereby industriallyscalable.
In an embodiment, the present invention provides a process for the preparation of substantially pureGlycine tert-butyl ester and its salt of formula (I) is illustrated in the following synthetic scheme.
(II) (III) (IV) (I)
The term “substantially pure” Glycine tert-butyl ester and its saltof formula (I) mentioned herein contains purity more than 96%; preferably more than 99%.
In another embodiment, the present invention provides an improved process for preparation of compound (IV) by reacting commercially available reagents such as potassium or sodium phthalimide and tert-butyl halo acetate in presence of inorganic base and without use of costly catalyst.
In another embodiment of the present invention, wherein the tert-butyl halo acetate is selected from tert-butyl chloro acetate, tert-butyl bromoacetate and tert-butyl iodoacetate; more preferably tert-butyl chloroacetate.
In another embodiment of the present invention, wherein the inorganic base in step (a) is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (CS2CO3), potassium carbonate (K2CO3), and sodium carbonate (Na2C03).
In another embodiment of present invention, wherein solvent in step (a) is selected from N,N- dimethylformamide (DMF), toluene, eye lo hexane, 77-hcptanc, mo no-halo benzenes such as monochlorobenzene, dihalobenzenes such as dichlorobenzene, dialkyl (CfCi2) ethers, and the like; more preferably N,N-dimethylformamide.
In another embodiment of present invention, wherein hydrocarbon solvent is selected from toluene, cyclohexane, 77-heptane, pentane and the like; more preferably 77-heptane.
In another embodiment of the present invention, wherein the preparation of compound (IV) is carried out at a temperature20°C to 80°C.
In another embodiment of the present invention, wherein the purification of compound (IV) is carried out at a temperature 20°C to 100°C.
In another embodiment of the present invention, wherein the base used inthe preparation of compound (I) isselected from hydrazine hydrate, hydrazine mono hydrate, and triethyl amine; preferably hydrazine mono-hydrate.
In another embodiment of the present invention, wherein the chlorinated solvent is selected from chloroform, dichloromethane, dichloroethane and the like.
In another embodiment of the present invention, wherein an acidis selected from hydrochloric acid in 1,4-dioxane, hydrochloric acid in hexane, hydrochloric acid in methanol, hydrochloric acid in toluene, hydrochloric acid in isopropyl alcohol; preferably in hydrochloric acid in 1,4- dioxane.
In another embodiment of the present invention, wherein aketonic solvent is selected from acetone, methyl ethyl ketone, acetophenone, cyclopentanone, 2-pentanone, preferablyacetone.
In another embodiment of the present invention, wherein preparation ofsubstantially pure compound (I) is carried out at a temperature between 20°C to 30°C.
In another embodiment of the present invention, wherein the purification of substantially purecompound (I) is carried out at a temperature 0°C to 30°C.
The preparation of the starting material used in the present invention is well known in prior art.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
EXAMPLES:
1) Preparation of compound (IV).
In a solution of compound (II) (1.3Kg) in DMF (2.0L), a powder potassium carbonate (4.58 g) was added at 20°C to 30°C. A tert-butyl chloroacetate (1.0 Kg) was added dropwise at 20°C to 80°C for 1-2 hrs. The reaction mixture was allowed to cool to 20°C to 30°C and stirred for 4-8 hrs. The reaction completion was ensured by HPLC. After completion, the reaction mixture was quenched by adding water at 0°C to 10°C and stirred for 2-3 hrs. The reaction mixture was filtered and dried to obtain compound (IV) (yield: 2.14-2.2 Kg, 95-98%, HPLC purity 96-97%).
2) Purification of Compound (IV)
A compound of formula (IV) was charged into n-heptane(3-5V) at 20°C to 30°C. The mixture was heated at 90°C to 100 °C for 2 hrsand cooled to 20°C to 30°C and stirred for 2 hrs. The solution was filtered, washed with n-hcptanc (IV), dried to obtain pure compound formula (IV; yield: 1.9-2.14 Kg, 85-95%; HPLC purity 99.5%). Ή NMR (DMSO-d6): d 1.45
(s, 9H, (CH3)3), 4.32 (s, 2H, CH2), 7.72 (dd, J = 5.6, 3.2 Hz,2H, Ar-H), 7.86 (dd, J = 5.6, 3.2 Hz, 2H, Ar-H); LCMS-279 [M + H20]+.
3) Preparation of compound (I).
In a solution ofcompound (IV) (1.0 Kg) in dichloromethane (8.0 L), hydrazine mono hydrate (2.0 L) (95-99%)was added at 20°C to 30°C. The reaction mixture was stirred at 20°C to 30°C for 18-26 hrs. The reaction completion was ensured by HPLC. After completion, reaction mixture was quenched by adding water (8-10V)and organic layer separated. Aqueous layer extracted with dichloromethane (2V). Combined organic layer was washed with water (2V). The solvent was removedup to -2.5V. To above reaction mass, toluene (3V) was added at 40-45 °C and further distilled up to3V at 40°C to 45°C under vacuum.To this organic mass a solution of 4MHC1 in 1, 4-dioxane (0.7 to 1.0V) was added at 0°C to 10°C and stirred for 0.5 to lhr.The reaction mass was filtered, washed with tolueneand dried to obtain compound of formula (I) (yield: 417-482 g, 65-75% yield, 90-96% HPLC purity)
4) Purification of Compound (I)
A compound of formula (I) was charged into an acetone (2-3V) at 20°C to 30°C stirred for 2 hrs. The solution was cooled to 0°C to 5°C for 2 hrs. and precipitated compound was filtered, and dried to obtain pure compound formula (1)352-417 g, 55-60%; HPLC purity 99.8%)
Ή NMR (CDCL) -Ή NMR (DMSO-d6): d 1.44 (s, 9H, (CH3)3), 3.64 (s, 2H, CH2), 8.42 (bs, 3H, NH3C1), MS- 173 [M free amine + ACN]+.
Claims
CLAIM:
1) A process for the preparation of substantially pure Glycine tert-butyl ester and its salts of formula (I) comprising the steps of:
a) reacting a compound of formula (II) where M is Potassium or Calcium, with tert- butyl halo acetate of formula (III) to obtain compound of formula (IV) in presence of an inorganic base and solvent;
b) reacting compound of formula (IV) with base in presence of chlorinated solvent; c) treating with acid.
2) The process as claimed in claim 1, where compound of formula (IV) optionally purifying in a hydrocarbon solvent; and compound of formula (I) optionally purifying in a ketonic solvent.
3) The process as claimed in claim 1, wherein tert-butyl halo acetate is selected from tert-butyl chloro acetate, tert-butyl bromoacetate and tert-butyl iodoacetate.
4) The process as claimed in claim 1, wherein inorganic base used for preparation of compound (IV) is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (CS2CO3), potassium carbonate (K2CO3), and sodium carbonate (Na2C03); and base used in the preparation of compound (I) is selected from hydrazine hydrate, hydrazine mono hydrate, and triethyl amine.
5) The process as claimed in claim 1, wherein solvent used in step (a) is selected from N,N-dimethylformamide(DMF), toluene, cyclohexane, 77-heptane, mono- halobenzenes such as monochlorobenzene, dihalobenzenes such as dichlorobenzene
and dialkyl (CfCi2) ethers; and chlorinated solvent is selected from chloroform, dichloromethane, and dichloroethane.
6) The process as claimed in claim2, wherein hydrocarbon solvent is selected from toluene, cyclohexane, n-hcptanc, and pentane; and ketonic solvent is selected from acetone, methyl ethyl ketone, acetophenone, cyclopentanone, and 2-pentanone.
7) The process as claimed in claim 1, wherein acid is selected from hydrochloric acid in 1,4-dioxane, hydrochloric acid in hexane, hydrochloric acid in methanol, hydrochloric acid in toluene, and hydrochloric acid in isopropyl alcohol.
8) The process as claimed in claim 1, wherein substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 96%.
9) The process as claimed in claim 1, wherein substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 99%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU749825A1 (en) * | 1978-04-24 | 1980-07-23 | Ордена Ленина Институт Элементоорганических Соединений Ан Ссср | Method of preparing tert-butyl ester of n-phthalylglycine |
| CN101239922A (en) * | 2007-02-09 | 2008-08-13 | 凯莱英医药化学（天津）有限公司 | Production technique of tert-butyl glycinate adapted for industrial production |
-
2022
- 2022-04-11 WO PCT/IB2022/053352 patent/WO2022219485A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU749825A1 (en) * | 1978-04-24 | 1980-07-23 | Ордена Ленина Институт Элементоорганических Соединений Ан Ссср | Method of preparing tert-butyl ester of n-phthalylglycine |
| CN101239922A (en) * | 2007-02-09 | 2008-08-13 | 凯莱英医药化学（天津）有限公司 | Production technique of tert-butyl glycinate adapted for industrial production |
Non-Patent Citations (1)
| Title |
|---|
| CAVELIER FLORINE, MARC ROLLAND AND JEAN VERDUCCI: "An Efficient One Step Synthesis Of Tert-Butyl Glycinate And Tert-Butyl Sarcosinate", ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL: THE NEW JOURNAL FOR ORGANIC SYNTHESIS, vol. 26, no. 5, 1 January 1994 (1994-01-01), pages 608 - 610, XP055981327 * |
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