WO2020194337A2 - A process for the asymmetric synthesis of sitagliptin intermediate - Google Patents

A process for the asymmetric synthesis of sitagliptin intermediate Download PDF

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WO2020194337A2
WO2020194337A2 PCT/IN2020/050251 IN2020050251W WO2020194337A2 WO 2020194337 A2 WO2020194337 A2 WO 2020194337A2 IN 2020050251 W IN2020050251 W IN 2020050251W WO 2020194337 A2 WO2020194337 A2 WO 2020194337A2
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group
formula
solvent
compound
mixture
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WO2020194337A3 (en
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Benudhar PUNJI
Beeran SENTHILKUMAR
Chepuri VENKATA RAMANA
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Council Of Scientific And Industrial Research
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/08—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a process for the asymmetric synthesis of compound of Formula 2.
  • R 1 is selected from the group consisting of C(0)R or C(0)0R;
  • R is selected from the group consisting of CH3, ethyl, isopropyl and tert-butyl
  • R 2 is selected from the group consisting of straight or branched, substituted or unsubstituted
  • the present invention relates to an asymmetric hydrogenation of compound of Formula 2 by using new catalyst system., which provides desired product formation in a very cost effective way.
  • Sitagliptin marketed under the brand name Januvia among others by Merck, is a medication used to treat diabetes mellitus type 2.
  • Sitagliptin is an anti-diabetic drug that works by increasing levels of natural substances called incretins. Incretins help to control blood sugar by increasing insulin release, especially after a meal and decrease the amount of sugar liver makes.
  • Sitagliptin is chemically known as“(3R)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro- 5H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one”having
  • the main objective of the present invention is to provide a process for the asymmetric synthesis of compound of Formula 2.
  • R 1 is selected from the group consisting of C(0)R or C(0)OR
  • R is selected from the group consisting of C3 ⁇ 4, ethyl, isopropyl and tert-butyl
  • R 2 is selected from the group consisting of straight or branched, substituted or unsubstituted
  • Ci-Cio alkyl substituted or unsubstituted aryl groups.
  • Another objective of the present invention is to provide an asymmetric hydrogenation of compound of Formula 2 by using new catalyst system which provides desired product formation in a very cost effective way.
  • Another objective of the present invention is to provide one-pot process for the synthesis of compound of Formula 2, wherein said process involves cost effective and sustainable catalyst system for the asymmetric hydrogenation.
  • R 1 is selected from the group consisting of C(0)R or C(0)OR
  • R is selected from the group consisting of C3 ⁇ 4, ethyl, isopropyl and tert-butyl
  • R 2 is selected from the group consisting of straight or branched, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted aryl groups
  • R 1 is selected from the group consisting of C(0)R or C(0)OR
  • R is selected from the group consisting of C3 ⁇ 4, ethyl, isopropyl and tert-butyl
  • R 2 is selected from the group consisting of straight or branched, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted aryl groups
  • step b) adding solvent into the mixture of step a) followed by transferring into reactor; c) purging the reaction vessel of step b) with hydrogen gas to obtain a reaction mixture; d) stirring the reaction mixture from step c) under 25-50 bar pressure and 60-120°C for a period of 30-35 hr;
  • metal catalyst is selected from the group consisting of Ni(OAc) 2 , (PPh ) 2 NiCl 2 , Ni(OTf) 2 , Ni(COD) 2 , Ni(Cp) 2 , (DME)NiCl 2 , (DME)NiBr 2, Ni(acac) 2, (thf) 2 NiBr 2 and (DuPhos)Ni(OAc) 2 Fe-precursors, Co-precursors, Mn- precursors,
  • said metal catalyst is Ni(OAc) 2 .
  • said additive is selected from the group consisting of NH 4 I, NH 4 Br, Me 4 NI, E NI, 'Pr 4 NI, Bu 4 NI, and Bu 4 NBr KI, Nal, Lil and Csl.
  • said ligand is selected from the group consisting of:
  • said ligand is i?,i?-DuPhos and 5,5- DuPhos.
  • said solvent of step b) is selected from the group consisting of methanol, ethanol, isopropanol, THF and mixture thereof
  • said solvent of step d) is selected from the group consisting of polar, non-polar solvent or mixtures thereof.
  • polar solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate and mixtures thereof.
  • non-polar solvent is selected from the group consisting of, pentane, hexane, benzene, cyclohexane, toluene, dichloromethane, diethyl ether, and mixtures thereof.
  • the compound of Formula 2 is obtained with 67-95% yield and 75-87% ee.
  • the process of the present invention relates to an asymmetric hydrogenation by using cost effective and sustainable nickel catalyst system to produce compound of Formula 2.
  • the process of the present invention involves nickel based chiral catalyst to produce compound of Formula 2 with good yield and enantiomeric excess.
  • the process is depicted below in Scheme- 1.
  • R 1 is selected from the group consisting of C(0)R or C(0)OR
  • R is selected from the group consisting of CH3, ethyl, isopropyl and tert-butyl
  • R 2 is selected from the group consisting of straight or branched, substituted or unsubstituted
  • the simple cost effective, one pot process for the synthesis of compound of Formula 2 comprises of reacting compound of Formula 1 with metal catalyst, ligand additive in a suitable solvent under hydrogen pressure and suitable temperature to afford compound of Formula 2.
  • the present invention relates to a process for the asymmetric synthesis of sitagliptin intermediate compound of Formula 2. More particularly, the process of the present invention relates to an asymmetric hydrogenation by using very cost effective and sustainable nickel catalyst system to produce sitagliptin intermediate compound of Formula 2.
  • the process of the present invention involves nickel based chiral catalyst to produce sitagliptin intermediate compound of Formula 2 with good yield and enantiomeric excess.
  • the process is depicted below in Scheme- 1.
  • R 1 is selected from the group consisting of of C(0)R or C(0)OR
  • R is selected from the group consisting of C3 ⁇ 4, ethyl, isopropyl and tert-butyl
  • R 2 is selected from the group consisting of straight or branched, substituted or unsubstituted
  • Ci-Cio alkyl substituted or unsubstituted aryl
  • R 1 is selected from the group consisting of C(0)R or C(0)OR; R is selected from the group consisting of CH3, ethyl, isopropyl and tert-butyl
  • R 2 is selected from the group consisting of straight or branched, substituted or unsubstituted
  • step b) adding solvent into the mixture of step a) followed by transferring into reactor;
  • step c) purging the reaction vessel of step b) with hydrogen gas to obtain a reaction mixture; d) stirring the reaction mixture from step c) under 25-50 bar pressure and at a temperature 60-120°C for a period in the range of 30-35 hr to obtain a solution;
  • Metal catalyst is selected from the group comprising of Ni(OAc)2, (PPh3)2NiCl2, Ni(OTf)2, Ni(COD)2, Ni(Cp)2, Fe-precursors, Co-precursors or Mn-precursors.
  • Ni(OAc)2 is used as a metal catalyst.
  • Ligand is selected from the group of compounds consisting of;
  • R,R-DuPhos and S,S-DuPhos is used as Ligand.
  • Additive is selected from the group consisting of NH 4 I, NFLBr, Me 4 NI, Et 4 NI, 'Pr 4 NI, BU 4 NI, and Bu 4 NBr.
  • NH 4 I is used as an additive.
  • the solvent used at step b) may include alcohol solvent.
  • Alcohol solvent may include methanol, ethanol, isopropanol and mixtures thereof. In particularly preferred embodiment, methanol is used at step b).
  • the hydrogen pressure and suitable temperature used at step d) is the range of 25-50 bar pressure and at a temperature 60-120°C, respectively. In particularly preferred embodiment, 30 bar pressure and 70°C temperature is used at step d).
  • the solvent used to quench the reaction mixture at step e) may include polar (ester) solvent, non-polar solvent or mixtures thereof.
  • Polar (Ester) solvent may include ethyl acetate, isopropyl acetate, butyl acetate and mixtures thereof.
  • Non-polar solvents may include pentane, hexane, benzene, cyclohexane, toluene, dichloromethane, diethyl ether, and mixtures thereof.
  • Table 1 summarizes results obtained with methyl-ester substrate of Formula 1 with different catalyst, additives and reaction parameters like pressure and temperature.
  • Table 2 summarizes results obtained by using ethyl-ester substrate of compound of Formula 1 in a reaction with different additives, solvent pressure and temperature and keeping Ni(OAc)2 metal catalyst and DuPhos ligand constant.
  • Table 3 summarizes the results obtained by using l Butyl-ester substrate compound of Formula 1 and with different additives, solvent, pressure and temperature.
  • Metal catalyst Ni(OAc)2 and DuPhos ligand kept constant.
  • Table 4 summarizes the results obtained by using alpha-methoxyphenyl-ester substrate compound of Formula 1 and with different additives, solvent, pressure and temperature.
  • Metal catalyst Ni(OAc)2 and DuPhos ligand kept constant.
  • Table 4 shows results of scaling up the asymmetric hydrogenation of N-Boc protected methyl ester.
  • the process of the present invention provides alternative catalyst system for highly costly and less-abundant transition metal catalyst, such as rhodium
  • the employed transition metal is highly abundant in earth-crust, thus, the process will be highly sustainable.

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  • Organic Chemistry (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The present invention relates to a process for the asymmetric synthesis of compound of Formula 2. wherein, R1 is selected from the group consisting of C(O)R or C(O)OR; R is selected from the group consisting of CH3, ethyl, isopropyl and tert-butyl R2 is selected from the group consisting of straight or branched, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted aryl groups. More particularly, the present invention relates to an asymmetric hydrogenation of compound of Formula 2 by using new catalyst system, which provides desired product formation in a very cost effective way.

Description

A PROCESS FOR THE ASYMMETRIC SYNTHESIS OF SITAGLIPTIN
INTERMEDIATE
FIELD OF THE INVENTION
The present invention relates to a process for the asymmetric synthesis of compound of Formula 2.
Figure imgf000002_0001
wherein,
R1 is selected from the group consisting of C(0)R or C(0)0R;
R is selected from the group consisting of CH3, ethyl, isopropyl and tert-butyl
R2 is selected from the group consisting of straight or branched, substituted or unsubstituted
C1-C10 alkyl, substituted or unsubstituted aryl groups.
More particularly, the present invention relates to an asymmetric hydrogenation of compound of Formula 2 by using new catalyst system., which provides desired product formation in a very cost effective way.
BACKGROUND AND PRIOR ART OF THE INVENTION
Sitagliptin, marketed under the brand name Januvia among others by Merck, is a medication used to treat diabetes mellitus type 2. Sitagliptin is an anti-diabetic drug that works by increasing levels of natural substances called incretins. Incretins help to control blood sugar by increasing insulin release, especially after a meal and decrease the amount of sugar liver makes. Sitagliptin is chemically known as“(3R)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro- 5H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one”having
C16H15F6N5O as a molecular formula and is structurally shown by Formula I below.
Figure imgf000002_0002
Formula I Known processes in the art for the synthesis of sitagliptin involves an expensive rhodium catalyst in the crucial asymmetric hydrogenation step that increases the cost of sitagliptin drastically. Several different catalyst systems involving costly transition metal catalysts like Rh, Ru, Ir etc. are known in the art for the asymmetric hydrogenation step to synthesize sitagliptin.
The article titled“Highly Efficient Asymmetric Synthesis of Sitagliptin” by Hansen, Karl B et. al and published in the journal“/. Am. Chem. Soc., 2009, 131 (25), pp 8798-8804” reports asymmetric hydrogenation of dehydrositagliptin intermediate to produce sitagliptin with 82% yield and >99.6 wt % purity by using as low as 0.15 mol % of Rh(I)/tBu JOSIPHOS.
The article titled“Mechanistic Insight into Asymmetric Hetero-Michael Addition of a, b- Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas” by Noboru Hayama et. al reports synthesis of sitagliptin by asymmetric hydrogenation of an dehydro intermediate by using chiral thioureas bearing both arylboronic acid and tertiary amine groups along with BnONH2 as a catalyst system.
Prior art processes involve very costly and complex transition metal catalyst systems for the preparation sitagliptin that produces extra industrial waste with tedious work ups making the hazardous impact on the environment and increases manufacturing cost.
Therefore, there is a need in the art to develop an inexpensive and sustainable catalyst system that can be used in the asymmetric hydrogenation of sitagliptin intermediates.
OBJECTS OF THE INVENTION
The main objective of the present invention is to provide a process for the asymmetric synthesis of compound of Formula 2.
Figure imgf000003_0001
wherein,
R1 is selected from the group consisting of C(0)R or C(0)OR;
R is selected from the group consisting of C¾, ethyl, isopropyl and tert-butyl
R2 is selected from the group consisting of straight or branched, substituted or unsubstituted
Ci-Cio alkyl, substituted or unsubstituted aryl groups. Another objective of the present invention is to provide an asymmetric hydrogenation of compound of Formula 2 by using new catalyst system which provides desired product formation in a very cost effective way.
Another objective of the present invention is to provide one-pot process for the synthesis of compound of Formula 2, wherein said process involves cost effective and sustainable catalyst system for the asymmetric hydrogenation.
SUMMARY OF THE INVENTION
The main embodiment of the present invention, a one-pot process for the asymmetric synthesis of compound Formula 2,
Figure imgf000004_0001
Formula 2
wherein,
R1 is selected from the group consisting of C(0)R or C(0)OR;
R is selected from the group consisting of C¾, ethyl, isopropyl and tert-butyl
R2 is selected from the group consisting of straight or branched, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted aryl groups
wherein said process comprises the steps of:
a) mixing compound of Formula 1,
Figure imgf000004_0002
Formula (1 )
R1 is selected from the group consisting of C(0)R or C(0)OR;
R is selected from the group consisting of C¾, ethyl, isopropyl and tert-butyl
R2 is selected from the group consisting of straight or branched, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted aryl groups
metal catalyst, ligand and additive in reaction vessel under an argon atmosphere to obtain a mixture;
b) adding solvent into the mixture of step a) followed by transferring into reactor; c) purging the reaction vessel of step b) with hydrogen gas to obtain a reaction mixture; d) stirring the reaction mixture from step c) under 25-50 bar pressure and 60-120°C for a period of 30-35 hr;
e) releasing the hydrogen pressure and quenching with solvent to obtain a product;
f) purifying the product of step e) by column chromatography using eluent (pet ether: ethyl acetate=10:l) to afford compound of Formula 2.
In an embodiment of the present invention, metal catalyst is selected from the group consisting of Ni(OAc)2, (PPh )2NiCl2, Ni(OTf)2, Ni(COD)2, Ni(Cp)2, (DME)NiCl2, (DME)NiBr2, Ni(acac)2, (thf)2NiBr2and (DuPhos)Ni(OAc)2Fe-precursors, Co-precursors, Mn- precursors,
In another embodiment of the present invention, wherein said metal catalyst is Ni(OAc)2.
In yet another embodiment of the present invention, said additive is selected from the group consisting of NH4I, NH4Br, Me4NI, E NI, 'Pr4NI, Bu4NI, and Bu4NBr KI, Nal, Lil and Csl.
In still another embodiment of the present invention, said ligand is selected from the group consisting of:
Figure imgf000005_0001
In an preferred embodiment of the present invention, said ligand is i?,i?-DuPhos and 5,5- DuPhos. In another embodiment of the present invention, said solvent of step b) is selected from the group consisting of methanol, ethanol, isopropanol, THF and mixture thereof
In an embodiment of the present invention, said solvent of step d) is selected from the group consisting of polar, non-polar solvent or mixtures thereof.
In another embodiment of the present invention, polar solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate and mixtures thereof.
In yet another embodiment of the present invention, non-polar solvent is selected from the group consisting of, pentane, hexane, benzene, cyclohexane, toluene, dichloromethane, diethyl ether, and mixtures thereof.
In a prefered embodiment of the present invention, the compound of Formula 2 is obtained with 67-95% yield and 75-87% ee.
In another embodiment of the present invention, a new one -pot process for the asymmetric synthesis of compound of Formula 2.
In yet another embodiment of the present invention, the process of the present invention relates to an asymmetric hydrogenation by using cost effective and sustainable nickel catalyst system to produce compound of Formula 2.
In still an embodiment of the present invention, the process of the present invention involves nickel based chiral catalyst to produce compound of Formula 2 with good yield and enantiomeric excess. The process is depicted below in Scheme- 1.
Figure imgf000006_0001
Scheme- 1
wherein,
R1 is selected from the group consisting of C(0)R or C(0)OR;
R is selected from the group consisting of CH3, ethyl, isopropyl and tert-butyl
R2 is selected from the group consisting of straight or branched, substituted or unsubstituted
C1-C10 alkyl, substituted or unsubstituted aryl groups.
In another embodiment of the present invention, the simple cost effective, one pot process for the synthesis of compound of Formula 2 comprises of reacting compound of Formula 1 with metal catalyst, ligand additive in a suitable solvent under hydrogen pressure and suitable temperature to afford compound of Formula 2.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention relates to a process for the asymmetric synthesis of sitagliptin intermediate compound of Formula 2. More particularly, the process of the present invention relates to an asymmetric hydrogenation by using very cost effective and sustainable nickel catalyst system to produce sitagliptin intermediate compound of Formula 2.
The process of the present invention involves nickel based chiral catalyst to produce sitagliptin intermediate compound of Formula 2 with good yield and enantiomeric excess. The process is depicted below in Scheme- 1.
Figure imgf000007_0001
Scheme- 1
wherein,
R1 is selected from the group consisting of of C(0)R or C(0)OR;
R is selected from the group consisting of C¾, ethyl, isopropyl and tert-butyl
R2 is selected from the group consisting of straight or branched, substituted or unsubstituted
Ci-Cio alkyl, substituted or unsubstituted aryl
The process of the present invention for the preparation of as depicted by Scheme- lcomprises of following steps:
a) mixing compound of Formula 1,
Figure imgf000007_0002
Formula (1 )
R1 is selected from the group consisting of C(0)R or C(0)OR; R is selected from the group consisting of CH3, ethyl, isopropyl and tert-butyl
R2 is selected from the group consisting of straight or branched, substituted or unsubstituted
C1-C10 alkyl, substituted or unsubstituted aryl groups
metal catalyst, ligand and additive in reaction vessel under an argon atmosphere to obtain a mixture;
b) adding solvent into the mixture of step a) followed by transferring into reactor;
c) purging the reaction vessel of step b) with hydrogen gas to obtain a reaction mixture; d) stirring the reaction mixture from step c) under 25-50 bar pressure and at a temperature 60-120°C for a period in the range of 30-35 hr to obtain a solution;
e) releasing the hydrogen pressure and quenching the solution with solvent to obtain a product;
f) purifying the product of step e) by column chromatography using eluent (pet ether: ethyl acetate=10:l) to afford compound of Formula 2.
Metal catalyst is selected from the group comprising of Ni(OAc)2, (PPh3)2NiCl2, Ni(OTf)2, Ni(COD)2, Ni(Cp)2, Fe-precursors, Co-precursors or Mn-precursors. In particularly preferred embodiment Ni(OAc)2 is used as a metal catalyst.
Ligand is selected from the group of compounds consisting of;
Figure imgf000008_0001
In particularly preferred embodiment R,R-DuPhos and S,S-DuPhos is used as Ligand.
Additive is selected from the group consisting of NH4I, NFLBr, Me4NI, Et4NI, 'Pr4NI, BU4NI, and Bu4NBr. In particularly preferred embodiment, NH4I is used as an additive. The solvent used at step b) may include alcohol solvent. Alcohol solvent may include methanol, ethanol, isopropanol and mixtures thereof. In particularly preferred embodiment, methanol is used at step b).
The hydrogen pressure and suitable temperature used at step d) is the range of 25-50 bar pressure and at a temperature 60-120°C, respectively. In particularly preferred embodiment, 30 bar pressure and 70°C temperature is used at step d).
The solvent used to quench the reaction mixture at step e) may include polar (ester) solvent, non-polar solvent or mixtures thereof. Polar (Ester) solvent may include ethyl acetate, isopropyl acetate, butyl acetate and mixtures thereof. Non-polar solvents may include pentane, hexane, benzene, cyclohexane, toluene, dichloromethane, diethyl ether, and mixtures thereof.
Several reactions have been conducted by using different substrate ester compounds of Formula 1, different additives and different metal catalysts that are summarized below. Reaction gives good yield and enantiomeric excess by using ethyl ester substrate of compound of Formula 1, NH4I additive, and Ni(OAc)2 catalyst with DuPhos ligand in methanol solvent.
Table 1 summarizes results obtained with methyl-ester substrate of Formula 1 with different catalyst, additives and reaction parameters like pressure and temperature.
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000010_0002
Table 1
Table 2 summarizes results obtained by using ethyl-ester substrate of compound of Formula 1 in a reaction with different additives, solvent pressure and temperature and keeping Ni(OAc)2 metal catalyst and DuPhos ligand constant.
Figure imgf000010_0001
Figure imgf000010_0003
Table 2
Table 3 summarizes the results obtained by using lButyl-ester substrate compound of Formula 1 and with different additives, solvent, pressure and temperature. Metal catalyst Ni(OAc)2 and DuPhos ligand kept constant.
Figure imgf000011_0001
,
Figure imgf000011_0003
Table 3
Table 4 summarizes the results obtained by using alpha-methoxyphenyl-ester substrate compound of Formula 1 and with different additives, solvent, pressure and temperature. Metal catalyst Ni(OAc)2 and DuPhos ligand kept constant.
F
Figure imgf000011_0002
solvent ( . mL)
T (°C), t (h)
Figure imgf000011_0004
Table 4 Table 5 shows results of scaling up the asymmetric hydrogenation of N-Boc protected methyl ester.
Figure imgf000012_0001
Figure imgf000012_0002
Table 5
EXAMPLES
Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.
Example 1: synthesis of compound of Formula 2:
An oven dried glass vials was transferred to the argon filled glove box, substrate compound of Formula 1 (methyl ester derivative of Formula 1 is used) (0.05 g, 0.144 mmol), Ni(OAc)2 (0.0012 g, 0.0072 mmol), 5,5-Duphos or R,R-Duphos (0.0026 g, 0.0086 mmol) and NFLT (0.0104 g, 0.072 mmol) were added to the reaction vial inside the glove box. Reaction vial was taken out and kept in reactor under argon atmosphere and methanol (2mL) was added in to it. Subsequently reactor purged three times with hydrogen gas. Finally reactor was pressurized with 30 bar hydrogen gas and stirred in preheated oil bath (70 °C) for 30 hours. After completion of the reaction, hydrogen pressure was released slowly and reaction quenched with ethyl acetate. Product formation confirmed by TLC and enantiomeric excess checked by HPLC. Purification by column chromatography (neutral alumina, PE : EA = 10:1) afforded the product as colorless solid; Yield: 88%. M.P. =90-92 °C. H NMR (500 MHz, CDCh) d = 7.07 (q, J = 9.2, 7.6, 1H), 6.92 (m, 1H), 5.12 (d, J = 7.63 Hz,IH), 4.14 (m, 1H), 3.71 (s, 3H), 2.86 (d, J = 6.87 Hz, 2H ), 2.54 (d, J = 8.8 Hz, 2H), 1.38 (s, 9H). 13C NMR (125 MHz, CDCb): 171.9 (COOMe), 155.1 (COOlBu), 119.2, 119.2, 119.0, 105.7, 105.5, 105.4, 79.7, 51.9, 47.8, 37.9, 33.1, 28.3.
HPLC: Chiralpack IC column; n-Hexane:MeOH:Ethyl acetate (97:3:0.1); lml/min; 266nm; 80% enantiomeric excess.
ADVANTAGES OF THE INVENTION
• One pot, simple, cost effective process for the preparation of sitagliptin intermediate
• The process of the present invention provides alternative catalyst system for highly costly and less-abundant transition metal catalyst, such as rhodium
• New catalyst system is highly sustainable and cheap.
• The employed transition metal is highly abundant in earth-crust, thus, the process will be highly sustainable.

Claims

WE CLAIM
1. A one-pot process for asymmetric synthesis of compound Formula 2,
Figure imgf000014_0001
Formula 2
wherein,
R1 is selected from the group consisting of C(0)R or C(0)OR;
R is selected from the group consisting of CH3, ethyl, isopropyl and tert-butyl
R2 is selected from the group consisting of straight or branched, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted aryl groups
wherein said process comprises the steps of:
a) mixing compound of Formula 1,
Figure imgf000014_0002
Formula (1 )
metal catalyst, ligand and additive in reaction vessel under an argon atmosphere to obtain a mixture;
b) adding solvent into the mixture of step a) followed by transferring into reactor;
c) purging the reaction vessel of step b) with hydrogen gas to obtain a reaction mixture; d) stirring the reaction mixture from step c) under 25-50 bar pressure and at a temperature 60-120°C for a period in the range of 30-35 hr to obtain a solution;
e) releasing the hydrogen pressure and quenching the solution with solvent to obtain a product;
f) purifying the product of step e) by column chromatography using eluent (pet ether: ethyl acetate=10:l) to afford compound of Formula 2.
2. The process as claimed in claim 1, wherein metal catalyst is selected from the group consisting of Ni(OAc)2, (PPh )2NiCl2, Ni(OTf)2, Ni(COD)2, Ni(Cp)2, (DME)NiCl2, (DME)NiBr2, Ni(acac)2, (thf)2NiBr2and (DuPhos)Ni(OAc)2 Fe-precursors, Co-precursors or Mn-precursors,
3. The process as claimed in claim 1, wherein said additive is selected from the group consisting of NH4I, NH4Br, Me4NI, EUNI, 'Pr4Nh Bu4NI, and Bu4NBr, KI, Nal, Lil and Csl.
4. The process as claimed in claim 1, wherein said ligand is selected from the group consisting of:
Figure imgf000015_0001
5. The process as claimed in claim 4, wherein said ligand is i?,i?-DuPhos and 5,5-DuPhos.
6. The process as claimed in claim 1, wherein said solvent of step b) is selected from the group consisting of methanol, ethanol, isopropanol, THF either alone or mixture thereof.
7. The process as claimed in claim 1, wherein said solvent of step d) is selected from the group consisting of polar, non-polar solvent either alone or mixture thereof.
8. The process as claimed in claim 7, wherein polar solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate.
9. The process as claimed in claim 7, wherein non-polar solvent is selected from the group consisting of, pentane, hexane, benzene, cyclohexane, toluene, dichloromethane, diethyl ether.
10. The process as claimed in claim 1, wherein the compound of Formula 2 is obtained with 67-95% yield and 75-87% ee.
PCT/IN2020/050251 2019-03-28 2020-03-18 A process for the asymmetric synthesis of sitagliptin intermediate WO2020194337A2 (en)

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