Claims:WE CLAIM:
1. A novel process for preparation of crystalline Form ‘A’ of the compound 8-(3R)-
3-aminopiperidinyl)-7-butyn-2-yl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-
3,7-dihydro purine-2,6-dione or 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-
7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl) xanthine, which comprises the
steps of:
i. dissolving any polymorphic form of Linagliptin in an aliphatic halogenated
hydrocarbon which is selected from methylene chloride, chloroform or carbon
tetrachloride or a mixture thereof;
ii. slowly adding the solution of step i. to an aliphatic straight chain or branched
chain ether which is selected from dimethyl ether, diethyl ether, diisopropyl ether
or methyl tert butyl ether or a mixture thereof, under stirring;
iii. stirring of reaction mass to ensure complete crystallization;
iv. isolating the product as wet cake by routine filtration/centrifugation; and
v. drying of wet cake at 50-60°C to give crystalline Form A.

Description:FIELD OF THE INVENTION:
The present invention discloses new polymorph of Linagliptin along with novel
processes for various polymorphs of Linagliptin. It also reports an improved
methodology for large scale production of highly pure Linagliptin. The process/
technology described herein is capable of producing highly pure Linagliptin
consistently.
BACKGROUD OF THE INVENTION:
Linagliptin, namely 8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3-methyl-1-(4-
methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione or 1-[(4-Methylquinazolin-
2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino- piperidin-1-yl)
xanthine, of formula I, is a long acting inhibitor of dipeptidylpeptidase-IV (DPP-IV)
activity, at present under development for the treatment of type II diabetes mellitus.
Its international nonproprietary name is Linagliptin [CAS number: 668270-12-0], has
the following chemical structure of formula I.
N
N N
N
N
O
O
CH3
N
N
CH3
NH2
Formula I
U.S. Patent No. 7,407,955 (US '955) discloses Linagliptin, related compounds, and
their pharmaceutical compositions. Further, it describes a process for the preparation
3
of Linagliptin wherein tert-butyloxy carbonyl (Boc) protectedLinagliptin is
deprotected using 5-6 M isopropanolic hydrochloric acid or equivalent acid, followed
by purification using chromatography. The process disclosed in US '955 is
schematically represented in scheme-l.
Scheme-1
U.S. Patent No. 7,820,815 ("US '815) discloses a process for preparation of
Linagliptin wherein it is prepared by deprotecting 1 -[(4-methyl-quinazolin-2-
yl)methyl]-3- methyl-7-(2-butyn-1 -yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthine
in presence of ethanolamine. The 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-
(2-butyn-1-yl)-8-(3-(R)phthalimidopiperidin-1-yl)-xanthine is prepared by
condensing 1-[(4- l methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
bromoxanthine with (R)-3-phthalimidopiperidine. The process disclosed in US '815 is
schematically represented in scheme-II.
4
Scheme II
The prior art processes as disclosed in US '955 and US '815 involve protectiondeprotection
method, leading to an increase in the manufacturing cycle time, decrease
in the product yield and further requires purification by chromatography that is not
suitable for commercial-scale manufacturing. In addition to this, the prior art
processes leads to the formation of bromo butene impurity (i.e. 1 -[(4-Methylquinazolin-
2-yl)methyl]-3- methyl-7-(3-bromobut-2-e -1 -yl)-8-(3-(R)-aminopiperidin-
1 -yl) xanthine of formula II as well as TFAL impurity of formula III.
Formula II
5
N
N
N
N
O
O
CH3
N
N
CH3
N
NH
O
F
F
F
Formula III: Trifluoro acetyl amino Linagliptin / TFAL
Linagliptin is known to exhibit polymorphism and is available in various
polymorphic forms e.g. US 9,266,888 or US2007 0259900 of Boehringer claims two
anhydrous forms A & B. It involves crude Linagliptin refluxing in ethanol and its hot
filtration after charcoalization followed by cooling of the filtrate to 20 °C & addition
of MTBE at <5°C to give anhydrous form A. This anhydrous form A on cooling
below 10 °C, leads to the formation of anhydrous form B. Furthermore, Forms C, D
& E are also reported. The crude Linagliptin is refluxed in methanol followed by its
charcoaling and then filtrate is distilled off to get residue. The resulting residue is
cooled to 45-55 °C followed by addition of MTBE and further cooling to 20-25 °C to
get Form C of Linagliptin. Further cooling of Form C to 0-5 °C to enhance
crystallization, Form D & E can be obtained.
US Patent Application US2013/0123282 of Teva, discloses preparation of amorphous
Linagliptin which involves partial dissolution of Linagliptin in ethanol followed by
evaporation of solvent under reduced pressure to get amorphous Linagliptin.
PCT patent application WO2013128379 of Dr. Reddy Limited reports heating of
Linagliptin in ethanol and heating to 78-79°C to get clear solution followed by its fine
filtration. The filtrate upon cooling below -10 °C to get Form I of Linagliptin.
6
Linagliptin Form II is reported to form by dissolution of Linagliptin in Methanol on
heating followed by its recrystallization by slow addition of MTBE.
Another US Patent Application US2013/0123282 of Teva, reports preparation of
various new Crystalline forms II, III, IV, V, VI, VII, VIII, IX, X, XI, XI’, XII, XIII,
XIII’, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII & XXIV using
amorphous Linagliptin.
SUMMARY OF THE INVENTION:
The present invention relates to an improved process for synthesis of Linagliptin,
which give highly pure Linagliptin in high yield. The traditional approach of making
Linagliptin using intermediate tert-butyl-[(3R)-1-{7-(but-2-yn-1-yl)-3-methyl-1-[(4-
methylquinazolin-2-yl)methyl] -2,6-dioxo-2,3,6,7-tetra hydro-1H-purin-8-
yl}piperidin-3-yl]carbamate or 8-[(3R)-3-Boc-amino piperidin-1-yl]-7-(but-2-yn-1-
yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H -purine-2,6-dione
as described in Scheme I or analogously in Scheme II involves deprotection using
Trifluoroacetic acid and quenching by aq sodium hydroxide. But it results in
increased TFAL impurity formation which once formed, is very difficult to reduce.
Therefore, according to present invention to sort out this problem, various organic as
well as inorganic base like TEA, DIPEA, LiOH, KOH, Ca(OH)2 were used for
quenching of reaction mass after deprotection with TFA but only the aq potassium
hydroxide along with modified process was able to control the formation of TFAL
impurity (Formula III). In other words, the modified/ improved process describes
herein, resulted in highly pure Linagliptin with controlled TFAL as well as BBL
impurities.
The present invention also reports the novel processes for the synthesis of various
known polymorphic forms of Linagliptin e.g. novel process developed for the
7
preparation of form A & C of Linagliptin basically involves dissolution of any
polymorphic form of Linagliptin in an aliphatic straight or branched chain alcohol
such as methanol and an halogenated hydrocarbon containing 2-5 carbon atoms such
as methylene chloride respectively, followed by the addition of resulting solution in
an aliphatic ether with stirring to give Linagliptin form A and Form C respectively.
The present invention also relates to one new polymorphic form of Linagliptin
developed by Morepen and designated it as “Form M”. Its synthesis involves
dissolution of any form of Linagliptin in either a halogenated hydrocarbon such as
methylene chloride or and aliphatic straight chain or branched chain alcohol such as
methanol, followed by its complete recovery under vacuum to obtain New crystalline
form M of Linagliptin.
BRIEF DESCRIPTION OF THE DRAWINGS:
The novel features of the invention are set forth with particularity in the claims that
follow. A better understanding of the features and advantages of the present invention
will be obtained by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention are utilized, and the
accompanying drawings of which:
1) Figure 1 shows the XRD of Linagliptin Form A
2) Figure 2 shows the XRD of Linagliptin Form B
3) Figure 3 shows the XRD of Morepen’s Linagliptin Form M
8
DETAILED DESCRIPTION OF THE INVENTION:
The various embodiments will be described in detail with reference to the
accompanying drawings. References made to particular examples and
implementations are for illustrative purposes, and are not intended to limit the scope
of the invention or the claims.
According to the first embodiment of the present invention, an improved process for
preparation of Linagliptin “8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-
dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione or
Linagliptin” which comprises:
1) A solution of tert-butyl [(3R)-1-{7-(but-2-yn-1-yl)-3-methyl-1-[(4-
methylquinazolin-2-yl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-
yl}piperidin-3-yl]carbamate or 8-[(3R)-3-Boc-aminopiperidin-1-yl]-7-
(but-2-yn-1-yl)-3-methyl-1-[(4-methylquin azolin-2-yl)methyl]-3,7-
dihydro-1H-purine-2,6-dione in an halogenated hydrocarbon is distilled
azeotropically for removal of moisture
2) slow addition of Trifluoroacetic acid to the solution of step 1 at 0-5 °C.
3) stirring of the reaction mixture at 0-5 °C for 20-24 hours.
4) lowering of temperature to -15 °C after completion of reaction.
5) quenching of the of reaction mass by adding water.
6) separation of aq layer
7) adjusting pH of reaction mass to 12.5-14.0 using aq potassium hydroxide
solution at -15 °C temperature.
8) addition of further aq potassium hydroxide
9
9) layer separation & water washing of the organic layer at room temperature
10) complete recovery of organic solvent below 50 °C.
11) again triturated the oily mass using an C1-C4 aliphatic straight chain or
branched chain alcohol so as to remove traces of solvent keeping
temperature Below 50 °C.
12) cooling the reaction mass to room temperature.
13) addition of an aliphatic C1-C4 straight chain or branched chain alcohol or a
mixture thereof.
14) stirring to ensure complete crystallization for 5-10 hours
15) isolation of product as wet cake by filtration.
16) drying the wet cake at 50-60 °C for 10-20 hours, till moisture content is
below desired level.
According to one aspect of the first embodiment, the quenching in 5 should be done
at -15°C to -10°C to control TFAL impurity.
According to another aspect of the first embodiment the pH in step 7 should be
towards higher range i.e. towards 14 to control TFAL impurity.
According to still another aspect of the first embodiment, the C1-C4 aliphatic straight
chain or branched chain alcohol used in step 11 & 13 is selected from methanol,
ethanol, 1-propanol, 2-propanol, butanol, Isopropyl alcohol, monoethylene glycol &
diethylene glycol or a mixture thereof.
According to still another aspect of first embodiment, the halogenated hydrocarbon
used in step 1 is selected from methylene chloride, chloroform or carbon tetrachloride
or a mixture thereof.
10
According to another aspect of first embodiment the pH in step 7 should be towards
higher range i.e. towards 14 to control TFAL impurity.
According to the second embodiment of the present invention, an improved process
for preparation of Linagliptin “8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-
dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione or
Linagliptin” which comprises:
1) A solution of tert-butyl [(3R)-1-{7-(but-2-yn-1-yl)-3-methyl-1-[(4-
methylquinazolin-2-yl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-
yl}piperidin-3-yl]carbamate or 8-[(3R)-3-Boc-aminopiperidin-1-yl]-7-
(but-2-yn-1-yl)-3-methyl-1-[(4-methylquin azolin-2-yl)methyl]-3,7-
dihydro-1H-purine-2,6-dione in an halogenated hydrocarbon is distilled
azeotropically for removal of moisture
2) slow addition of Trifluoroacetic acid to the solution of step 1 at 0-5 °C.
3) stirring of the reaction mixture at 0-5 °C for 20-24 hours.
4) lowering of temperature to -15 °C after completion of reaction .
5) quenching of the of reaction mass by adding water.
6) adjusting pH of organic layer reaction mass to 12.5-14.0 using aq
Potassium hydroxide solution at -15 °C temperature.
7) addition of further aq potassium hydroxide
8) layer separation & water washing of the organic layer at room temperature
9) complete recovery of organic solvent below 50 °C.
10) again triturated the oily mass using an C1-C4 aliphatic straight chain or
branched chain alcohol so as to remove traces of various solvent keeping
11
temperature round about 50 °C.
11) cooling the reaction mass to room temperature.
12) addition of an aliphatic C1-C4 straight chain or branched chain alcohol or a
mixture thereof.
13) stirring to ensure complete crystallization for 5-10 hours
14) isolation of product as wet cake by filtration
15) drying the wet cake at 50-60 °C for 10-20 hours, till moisture content is
below desired level.
According to one aspect of the second embodiment, the quenching in 5 should be
done at -15°C to -10°C to control TFAL impurity.
According to another aspect of the second embodiment, the pH in step 6 should be
towards higher range i.e. towards 14 to control TFAL impurity.
According to still another aspect of the second embodiment, the C1-C4 aliphatic
straight chain or branched chain alcohol used in step 10 & 12 is selected from
methanol, ethanol, 1-propanol, 2-propanol, butanol, Isopropyl alcohol, monoethylene
glycol & diethylene glycol or a mixture thereof.
According to another aspect of second embodiment, the halogenated hydrocarbon
used in step 1 is selected from methylene chloride, chloroform or carbon tetrachloride
or a mixture thereof.
According to the third embodiment of the present invention, a novel process for
preparation of Crystalline form A of Linagliptin “8-[(3R)-3-Amino-1-piperidinyl]-7-
(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1Hpurine-
2,6-dione or Linagliptin” which comprises:
12
i. dissolving any polymorphic form of Linagliptin in an aliphatic halogenated
hydrocarbon.
ii. slow addition of the solution of step (i) to an aliphatic ether under stirring
iii. stirring of reaction mass to ensure complete crystallization
iv. isolation of product as wet cake by filtration.
v. drying of wet cake at 50-60 °C to give Crystalline form A of Linagliptin
According to one aspect of third embodiment, the halogenated hydrocarbon used in
step (i) is selected from methylene chloride, chloroform or carbon tetrachloride or a
mixture thereof.
According to still another aspect of the third embodiment, the aliphatic straight chain
or branched chain ether used in step (ii) can be selected from dimethyl ether, diethyl
ether, diisopropyl ether or methyl tert butyl ether or a mixture thereof
XRD of form A obtained is as given in Fig 1 and have following peaks as given in
Table I below:
S.No 2 theta Relative intensity (%)
1. 7.246 32.47
2. 7.695 100.00
3. 8.614 17.93
4. 11.213 15.89
5. 11.725 44.73
6. 12.454 80.22
7. 15.302 15.68
8. 19.620 15.42
9. 22.494 17.47
10. 23.122 69.42
11. 25.173 62.97
12. 25.731 52.86
13. 28.849 23.67
13
According to the fourth embodiment of the present invention, a novel process for
preparation of Crystalline form C of Linagliptin “8-[(3R)-3-Amino-1-piperidinyl]-7-
(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl]-1Hpurine-
2,6-dione or Linagliptin” which comprises:
i. dissolving any polymorph of Linagliptin in a C1-C4 aliphatic straight chain or
branched chain alcohol
ii. slow addition of this solution of step 1 to an aliphatic ether under stirring
iii. stirring of reaction mass to ensure complete crystallization
iv. isolation of wet cake by filtration .
v. drying of wet cake at 50-60 °C to give Crystalline form C of Linagliptin
According to one aspect of the fourth embodiment, the C1-C4 aliphatic straight chain
or branched chain alcohol used in step (i) is selected from methanol, ethanol, 1-
propanol, 2-propanol, butanol, Isopropyl alcohol, monoethylene glycol & diethylene
glycol or a mixture thereof.
According to still another aspect of fourth embodiment, the aliphatic straight chain or
branched chain ether used in step (ii) can be selected from dimethyl ether, diethyl
ether, diisopropyl ether or methyl tert butyl ether or a mixture thereof
XRD of form C obtained is as given in Fig 2 and have following peaks as given in
Table II below:
S.No 2 theta Relative intensity (%)
1. 7.0054 100.00
2. 8.1910 54.64
3. 13.950 26.42
4. 22.693 15.75
5. 23.859 17.14
14
According to the fifth embodiment of the present invention, a novel polymorphic
form of Linagliptin designated as “form M” & process for preparation of Linagliptin
Form M is disclosed which comprises:
i. dissolving any polymorphic form of Linagliptin in a C1-C4 aliphatic straight
chain or branched chain alcohol or an aliphatic halogenated hydrocarbon.
ii. complete recovery of solvent under vacuum to obtain desired polymorphic
form M of Linagliptin.
According to one aspect of the fifth embodiment, the C1-C4 aliphatic straight chain or
branched chain alcohol used in step (i) is selected from methanol, ethanol, 1-
propanol, 2-propanol, butanol, Isopropyl alcohol, monoethylene glycol & diethylene
glycol or a mixture thereof.
According to another aspect of the fifth embodiment, the halogenated hydrocarbon
used in step (i) is selected from methylene chloride, chloroform or carbon
tetrachloride or mixture thereof.
XRD of form M disclosed herein is as given in Fig 3 and have following peaks as
given in Table III below
S.No 2 theta Relative intensity (%)
1. 7.249 15.72
2. 10.570 42.68
3. 13.549 16.49
4. 14.125 65.72
5. 15.642 35.65
6. 16.311 24.48
7. 16.690 52.02
8. 19.563 52.50
9. 20.112 30.26
10. 21.775 100.00
11. 23.250 38.14
12. 23.646 61.48
15
13. 24.350 47.38
14. 26.066 30.96
15. 26.55 15.29
16. 27.14 19.26
17. 27.261 15.33
18. 33.63 18.28
The above mentioned inventions are supported by the following non limiting
examples. Reference example 1 is given to give overview of existing Linagliptin
synthesis on the basis of various processes as discussed in prior art.
Reference Example 1:
The tert-butyl [(3R)-1-{7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-
yl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}piperidin-3-yl]carbamate or
8-[(3R)-3-Boc-amino piperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-
methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione (50 g) is dissolved
in methylene dichloride (500 ml) with stirring at 20-30 °C. The reaction solution is
heated & azeotropic recovery of methylene dichloride is done to remove moisture
followed by cooling of reaction mass to 0-5 °C. Then slow addition of Trifluoroacetic
acid (225 g) is done followed by stirring of the reaction mass for 15-20 hours at same
temperature. After reaction completion, the reaction mass is cooled to -15 °C and
quenching is done by addition of water to it followed by adjusting the pH to 9.5-10.5
using NaOH solution (70 g) with stirred & layer separation at room temperature. The
organic layer containing product is given three water washing followed by brine
washing. The recovery of solvent is done followed by isolation of Linagliptin in
MeOH-MTBE.
Yield = 0.55
Purity by HPLC = 99.27 %
16
Single highest impurity = 0.50 %
Total Impurities = 0.73%
Example 1:
tert-butyl [(3R)-1-{7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-
2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}piperidin-3-yl]carbamate or 8-[(3R)-3-
Boc-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-
yl)methyl]-3,7-dihydro-1H-purine-2,6-dione (50 g) is dissolved in methylene
dichloride (500 ml) with stirring at 20-30 °C. on heating followed by partial recovery
of methylene dichloride azeotripically to remove moisture. The resulting solution is
cooled to 0-5 °C and slowly added Trifluoroacetic acid (225 g) to it. The reaction
mixture is stirring for 15-20 hours at same temperature. After reaction completion,
the reaction mass is cooled to -15 °C and quenching by addition of water (350 ml) to
it followed by adjusing the pH to 12.5-14 using aq potassium hydroxide solution (120
g) and layer separation to discard aq layer followed by water and brine washing of the
organic layer containing product. Then complete recovery of solvent is done and
product Linagliptin is isolated in MeOH 25ml) and isopropyl alcohol (250ml)
followed by slurry washing of wet cake with Methyl tert-butyl ether (25 ml) and
drying at 50-60 °C for 12-15 hours to give pure Linagliptin.
Yield = 0.60
Purity by HPLC = 99.89 %
Single highest impurity = 0.06 %
TFAL Impurity = 0.05%
Total Impurities = 0.11 %
17
S-isomer = Not detected.
Example 2:
tert-butyl [(3R)-1-{7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-
2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}piperidin-3-yl]carbamate or 8-[(3R)-3-
Boc-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-
yl)methyl]-3,7-dihydro-1H-purine-2,6-dione (50 g) is dissolved in methylene
dichloride (500 ml) with stirring at 20-30 °C. on heating followed by partial recovery
of methylene dichloride azeotripically to remove moisture. The resulting solution is
cooled to 0-5 °C and slowly added Trifluoroacetic acid (225 g) to it. The reaction
mixture is stirring for 15-20 hours at same temperature. After reaction completion,
the reaction mass is cooled to -15 °C and quenching by addition of water (350 ml)
followed by layer separation to discard the aqueous layer & added water (50 ml) to
the organic layer, followed by adjusing the pH to 12.5-14 using aq potassium
hydroxide solution (120 g) and layer separation to discard aq layer followed by water
and brine washing of the organic layer containing product. Then complete recovery of
solvent is done and product Linagliptin is isolated in MeOH 25ml) and isopropyl
alcohol (250ml) followed by slurry washing of wet cake with Methyl tert-butyl ether
(25 ml) and drying at 50-60 °C for 12-15 hours to give pure Linagliptin.
Yield = 0.62
Purity by HPLC = 100.00%
Single highest impurity = 0.00 %
Total Impurities = 0.00 %
S-isomer = Not detected.
18
Example 3:
Linagliptin (4 g) is dissolved in methylene chloride (8 ml) and the resulting
Linagliptin solution is added to the Methyl tert butyl ether (20 ml) with stirring at 20-
30 °C in 10-15 minutes followed by stirring of reaction mass for 3-4 hours to ensure
complete crystallization. Then the reaction mass is cooled to 0-5 °C and product is
isolated by filtration and running washing of wet cake with methyl tert butyl ether (2
ml). The wet cake is dried at 50-60 °C for 6-7 hrs under vacuum to give Linagliptin
Form A having XRD reported in Figure 1 (Yield = 0.82).
Example 4:
Linagliptin (4 g) is dissolved in Methanol (8 ml) and the resulting Linagliptin
solution is added to the Methyl tert butyl ether (20 ml) with stirring at 20-30 °C in 10-
15 minutes followed by stirring of reaction mass for 3-4 hours to ensure complete
crystallization. Then the reaction mass is cooled to 0-5 °C and product is isolated by
filtration and running washing of wet cake with methyl tert butyl ether (2 ml). The
wet cake is dried at 50-60 °C for 6-7 hrs under vacuum to give Linagliptin Form C
having XRD reported in Figure 2 (Yield = 0.84).
Example 5:
Linagliptin (4 g) was dissolved in methylene chloride (8 ml) by stirring the reaction
mass for 20-30 minutes. The resulting solution was heated to 40-45 °C followed by
complete recovery of solvent under vacuum followed by its further drying at 50-60
°C for 6-7 hours to get new polymorphic form M of Linagliptin having XRD
reported in Figure 3.
19
Yield = 0.97
Example 6:
Linagliptin (4 g) was dissolved in Methanol (8 ml) by stirring the reaction mass for
20-30 minutes. The resulting solution was heated to 40-45 °C followed by complete
recovery of solvent under vacuum followed by its further drying at 50-60 °C for 6-7
hours to get new polymorphic form M of Linagliptin having XRD reported in Figure
4.
Yield = 0.94