AU2022201063B2 - The Method of the Preparation of Fused Multicyclic Compounds - Google Patents

The Method of the Preparation of Fused Multicyclic Compounds Download PDF

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AU2022201063B2
AU2022201063B2 AU2022201063A AU2022201063A AU2022201063B2 AU 2022201063 B2 AU2022201063 B2 AU 2022201063B2 AU 2022201063 A AU2022201063 A AU 2022201063A AU 2022201063 A AU2022201063 A AU 2022201063A AU 2022201063 B2 AU2022201063 B2 AU 2022201063B2
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Hsing-Pang Hsieh
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National Health Research Institutes
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives

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

Abstract

The present invention discloses a process for preparing compounds of Formula (I), particularly, a process manufacturing thereof on a multikilogram scale: H H HN BN N R2 W O R1 Z N (I) wherein B, D, W, Z, R1 , R2, and n are defined herein.

Description

The Method of the Preparation of Fused Multicyclic Compounds
BACKGROUND
[0001] Kinase inhibitors are a class of targeted anti-cancer drugs that block the
overexpressed and/or mutant kinase functions. US FDA (U.S.A. Food and Drug
Administration) has approved some inhibitors that target around 20 kinases (Roskoski,
Pharmacol. Res. 2020, 152, 104609). Additionally, numerous kinase inhibitors are
registered in clinical trials and are at different drug development phases (Lightfoot et.
al., ACS Med. Chem. Lett. 2018, 10, 153-160).
[0002] US 9,006,252 discloses a series of quinazoline-based compounds as
multi-kinase inhibitors with potent enzymatic and cellular activities in multiple solid
tumor cell lines and in vivo efficacy in leukemia, colorectal and pancreatic xenograft
mouse models upon intravenous administration. The reported synthetic route consisted
of seven steps from commercially available 2-amino-4-fluorobenzoic acid in milligram
yields. However, scale-up to gram-scale synthesis resulted in a decrease in yield.
[0003] There are also several drawbacks were identified during the scale-up
synthesis including: (i) variable yields during the chlorination and SNAr step and the
final dimethyl amination step, increases the overall cost of synthesis, (ii) the use of
unsafe reagent NaH/DMF and (iii) the requirement for several column chromatography
purifications steps. For pharmaceutical applications, it is necessary to seek an
alternative, safe, and efficient route to provide multi-kilograms of these compounds in
a high yield with easy to purify steps.
SUMMARY
[0004] As discussed above, there remains a need for the development of
robust scale-up synthetic route for quinazoline compounds. This invention relates to a
process for preparing a compound of Formula (I) or a pharmaceutically acceptable
salt thereof, wherein, B is an arylene or heteroarylene; D is an alkyl, alkenyl,
alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, or hetrocycloalkenyl group; W and Z is, independently, N
or CRa, Ra being hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetrocycloalkenyl
alkoxy, halogen, alkoxy amino, or alkoxy alkylamino group; R 1 and R 2 is,
independently, being hydrogen, halogen, or -OA, wherein R 1 and R 2 are not
both hydrogens; A is an alkylamino group; n is 0, 1, 2, 3, or 4; and the
process comprising: reacting a compound of Formula (II) with a compound
of Formula (III). In some preferred embodiments, the compound of Formula
(I) is recrystallized from solvents.
[0005] In certain embodiments, the process further comprising:
converting a compound of Formula (IV) to the compound of Formula (III).
In some preferred embodiments, the compound of Formula (III) is
recrystallized from solvents.
[0006] In certain embodiments, the process further comprising: reacting
a compound of Formula (V) with a compound of Formula (VI) to form a
compound of Formula (IV). In some preferred embodiments, the compound of
Formula (IV) is provided as solid by centrifugation.
[0007] In certain embodiments, the process further comprising:
converting a compound of Formula (VII) to the compound of Formula (VI).
In some preferred embodiments, the compound of Formula (VI) is provided by removing the compound of Formula (VII) from the mixture thereof using liquid-liquid extraction. In some preferred embodiments, the liquid-liquid extraction is conducted by adding ETOAc to the mixture and collecting the compound of Formula (VI) therein.
[0008] In certain embodiments, the process further comprising: reacting
a compound of Formula (VIII) with a alkanolamine to form a compound of
Formula (VII); wherein X and Y is, independently, being a halogen or
hydrogen, X and Y are not both hydrogens. In certain other embodiments, the
alkanolamine is a compound of Formula (IX), wherein A is L ,, NRbRc
wherein R and Rcis, independently, hydrogen, alkyl, alkenyl, alkynyl, aryl,
monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
hetrocycloalkenyl group; m is 2, 3, or 4. In some preferred embodiments, m is 3
and, each Rb and RC is methyl group. In some other preferred embodiments,
the compound of Formula (VII) is provided as solid by centrifugation.
[0009] In certain embodiments, the process further comprising: reacting
a compound of Formula (X) with formamidine acetate to form a compound
of Formula (VIII). In some preferred embodiments, the compound of Formula
(VIII) is provided as solid by centrifugation.
[0010] In some preferred embodiments, R2 is hydrogen.
[0011] In some preferred embodiments, B is phenyl or thiazolyl group. In
N
some other preferred embodiments, B is hS.
[0012] In some preferred embodiments, D is 6-membered aryl or
heteroaryl group. In some other preferred embodiments, D is ci,
I MeO', OMe C or CI.
[0013] In some preferred embodiments, R2 is hydrogen, A is 4 NRbR B
N
is X S , Dis CI, each W, and Z is CRa, Ra is hydrogen, n is 2, m is 3,
and each Rb and R° is methyl group.
[0014] H H HN N N 2 R W (
R1 N (I)
D-N=C=O
HN BNH2 2 R W
R1 Z N2 (III)
HN B,NHBoc
2 R W
R1 Z N (IV)
BBV H 2N
CI R2 W
R1 Z N (VI)
2 R W Y W NH
Z N (VII)
0
N H
X- Z N' (ViII)
A-OH (IX)
0
W OH
X Z NH 2 (X)
DEFINITIONS
[0015] In certain embodiments, the alkyl, alkenyl and alkynyl groups
employed in the invention contain about 1-20 aliphatic carbon atoms. In certain other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention
contain about 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl,
alkenyl, and alkynyl groups employed in the invention contain about 1-8 aliphatic
carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups
employed in the invention contain about 1-6 aliphatic carbon atoms. In yet other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention
contain about 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not
limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl,
isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2 buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
[0016] The term "cycloalkyl", as used herein, refers specifically to cyclic
alkyl groups having three to seven, preferably three to ten carbon atoms. Suitable
cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, heteroaliphatic
or heterocyclic moieties, may optionally be substituted. An analogous convention
applies to other generic terms such as "cycloalkenyl", "cycloalkynyl" and the like.
[0017] In general, the term "aryl" refers to aromatic moieties, as described
above, excluding those attached via an alkyl or heteroalkyl group. In certain
embodiments of the present invention, "aryl" refers to a mono- or bicyclic carbocyclic
ring system having one or two rings satisfying the Huckel rule for aromaticity,
including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl
and the like.
[0018] Similarly, the term "heteroaryl" refers to heteroaromatic group, as
described above, excluding those attached via an alkyl or heteroalkyl group. In certain
embodiments of the present invention, the term "heteroaryl", as used herein, refers to
a cyclic unsaturated radical having from about five to about ten ring atoms of which
one ring atom is selected from S, 0 and N; zero, one or two ring atoms are additional
heteroatoms independently selected from S, 0 and N; and the remaining ring atoms
are carbon, the radical being joined to the rest of the molecule via any of the ring
atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl,
furanyl, quinolinyl, isoquinolinyl, and the like.
[0019] Substituents for aryl and heteroaryl groups include, but are not limited
to, any of the previously mentioned substitutents, i.e., the substituents recited for
aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation
of a stable compound.
[0020] The terms alkoxy as used herein refers to an alkyl group, as previously
defined, attached to the parent molecular moiety through an oxygen atom. In certain
embodiments, the alkyl group contains about 1-20 aliphatic carbon atoms. In certain
other embodiments, the alkyl group contains about 1-10 aliphatic carbon atoms. In yet
other embodiments, the alkyl group contains about 1-8 aliphatic carbon atoms. In still
other embodiments, the alkyl group contains about 1-6 aliphatic carbon atoms. In yet
other embodiments, the alkyl group contains about 1-4 aliphatic carbon atoms.
Examples of alkoxy groups, include but are not limited to, methoxy, ethoxy, propoxy,
isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
[0021] The term "alkylamino" refers to a group having the structure -N(R)2
wherein each occurrence of R is independently hydrogen, or an aliphatic,
heteroaliphatic, aromatic or heteroaromatic group, or the R groups, taken together,
may form a heterocyclic group.
[0022] The terms "halo" and "halogen" as used herein refer to an atom
selected from fluorine, chlorine, bromine and iodine.
[0023] As used herein, the terms "alkyl", "alkenyl", "alkynyl", "heteroalkyl",
"heteroalkenyl", "heteroalkynyl", and the like encompass substituted and
unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly,
the terms "heterocycloalkyl", "heterocycle" and the like encompass substituted and
unsubstituted, and saturated and unsaturated groups. Additionally, the terms
"cycloalkyl", "cycloalkenyl", "cycloalkynyl", "heterocycloalkyl",
"heterocycloalkenyl", "heterocycloalkynyl", "aromatic", "heteroaromatic", "aryl",
"heteroaryl" and the like, used alone or as part of a larger moiety, encompass both
substituted and unsubstituted groups.
[0024] Compounds of this invention include those generally set forth above
and described specifically herein, and are illustrated in part by the various classes,
subgenera and species disclosed herein. The details of one or more embodiments of
the invention are set forth in the description below. Other features, objects, and
advantages of the invention will be apparent from the description and from the claims.
DETAILED DESCRIPTION
[0025] Shown below are exemplary compounds of this invention:
0
OH
F NH 2 Compound 1
0
NH
F N Compound 2
N ~OH Compound 3
N 0
NH
O0 N Compound 4
N CI
O N Compound 5
N
NHNHoc
N N HN HS
o N Compound 7
N I"'NH2 N HN S 3TFA NN
O N Compound 8
Cl C:N
Compound 9
NN I"'NH N HN NS
o N Compound 10
[0026] The previously reported medicinal chemistry synthetic route with
seven steps had encountered several issues during scale-up syntheses such as low
yields, the formation of inseparable impurities, particularly in the chlorination step,
use of hazardous reagents (NaH/DMF), and laborious column chromatography steps
for the purification of the products (Hsu, Y. C., et. al. Oncotarget 2016, 7, 86239
86256.). A step-by-step approach to overcome the above issues was planned in the
following examples.
Example 1
Synthesis of the compound of Formula (VIII) by condensation with
formamidine
[0027] The compound of Formula (VIII) can be obtained by reacting
the compound of Formula (X) with formamidine (Scheme 1); wherein W and
Z is, independently, N or CRa, Ra being hydrogen, alkyl, alkenyl, alkynyl, aryl,
monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetrocycloalkenyl
alkoxy, halogen, alkoxy amino, or alkoxy alkylamino group; wherein X and Y is,
independently, being a halogen or hydrogen, X and Y are not both
hydrogens. Preferably, the compound of Formula (VIII) is provided as solid
by centrifugation.
Scheme 1
0 0
OH Formamidine - NH
X Z NH 2 solvent X Z N
(X) (VIII)
[0028] As an example, the quinazolinone 2 was synthesized from the starting
material 1 by condensation with formamidine acetate. The following three conditions
were studied to optimize this reaction for a 10.0 g scale of starting material 1 (Table
1). In this reaction system, the resulting product 2 was not soluble in EtOH at room
temperature, facilitating the easy isolation of a pure product by simple filtration.
Table 1
Entry Solvent Time (h) Temp (°C) 3 Yield(%)
1 neat 12 120 63
2 DMSO 4 120 83
3 EtOH 40 reflux 93
[0029] The unreacted starting material 1 could be removed successfully in the
workup process. Once the reaction is completed, the batch temperature was gradually
decreased to about 10-15 °C and stirred for 4 h. The precipitated product was
centrifuged to get the cake, rinsed with cold EtOH, and dried under vacuum at 55 °C
for 24 h to afford 2.
[0030] 7-Fluoroquinazolin-4(3H)-one(2). 1H-NMR (400 MHz, DMSO-d6 ) 6
12.35 (brs, 1H), 8.16 (dd, J = 8.8, 6.4 Hz, 1H), 8.13 (s, 1H), 7.45 (dd, J= 10.4, 2.8 Hz,
1H), 7.39 (ddd, J= 8.4, 8.8, 2.4 Hz, 1H). 1 3 C NMR (100 MHz, DMSO-d 6 ), 6 166.8
164.3 (d, J= 249.3 Hz), 160.0, 150.9 (d, J= 13.0 Hz), 146.8, 128.9 (d, J= 10.7 Hz),
119.6, 115.2 (d, J= 23.7 Hz), 112.3 (d, J= 21.4 Hz). HRMS (ESI) calcd for
C 8H 5FN 2NaO [M + Na]: 187.0283; found 187.0283.
Example 2
Formation of the compound of Formula (VII) by SNAr attack with alkanolamine
[0031] The compound of Formula (VII) can be obtained by reacting
the compound of Formula (VIII) with alkanolamine in basic condition
(Scheme 2); wherein W and Z is, independently, N or CRa, Ra being hydrogen, alkyl,
alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, hetrocycloalkenyl alkoxy, halogen, alkoxy amino, or alkoxy
alkylamino group; R1 and R2 is, independently, being hydrogen, halogen, or -OA, wherein R 1 and R 2 are not both hydrogens; A is an alkylamino group; wherein X and
Y is, independently, being a halogen or hydrogen, X and Y are not both
hydrogens. In some embodiments, the alkanolamine has a Fomula (IX).
Preferably, the compound of Formula (VII) is provided as solid by
centrifugation.
Scheme 2
0 0 2 W R y W ~- NH alkanoaamine NH
X : Z ' base R (VIII) (VII)
[0032] Take the synthesis of 4 as an example, the reaction conditions were set
out to optimize for kilogram-scale synthesis (Table 2). The reaction could be
progressed in neat 3-(dimethylamino)propan-1-ol (3) using KOH as the base, the
reaction was quenched with water, and then the product 4 isolated by ethyl acetate
extraction in good yields (88% isolated yield) in a 10.0 g scale reaction.
Table 2
4
Entry 2 (g) Solvent Temp (C) Yield (%) Purity (%)
1 10.0 DMSO 140 55 98.5
2 10.0 DMSO 125 83 98.1
3 20.0 neat 120 73 98.4
4 560.0 neat 120 79 99.1
[0033] Preferably, a special apparatus (Reddy et. al., Org. Process Res. Dev.
2021, 25, 817-830) was used for the continuous extraction of the aqueous phase for a
longer time (3 days) using ethyl acetate or CH 2Cl 2. Continuous extraction with EtOAc
without adjustment of pH by adding 6 N HCl to the reaction mixture (pH >10)
provides the desired product 4 with relatively good yield and purity (after slurry
purification disposal).
[0034] 7-(3-(Dimethylamino)propoxy)quinazolin-4(3H)-one(4). IH-NMR
(400 MHz, DMSOd) 6 12.07 (brs, 1H), 8.04 (s, 1H), 8.00 (d, J= 9.6 Hz, 1H), 7.08 (t,
J = 7.6 Hz, 2H), 4.13 (t, J = 6.4 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H), 2.15 (s, 6H), 1.91
1.84 (in, 2H). 13 C-NMR (100 MHz, DMSO-d 6), 6 163.2, 160.2, 150.9, 145.9, 127.4,
116.3, 115.9, 108.8, 66.3, 55.5, 45.1, 26.6. HRMS (ESI) calcd for C13H8N302 [M
+ H]: 248.1399; found 248.1395.
Example 3
Production of the compound of Formula (VI) by chlorination
[0035] The compound of Formula (VI) can be obtained by chlorination
of the compound of Formula (VII) (Scheme 3); wherein W and Z is,
independently, N or CRa, Rbeing hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetrocycloalkenyl alkoxy,
halogen, alkoxy amino, or alkoxy alkylamino group; R1 andR2 is, independently,
being hydrogen, halogen, or -OA, wherein R 1 and R2 are not both hydrogens; A is an
alkylamino group; n is 0, 1, 2, 3, or 4. Typically, POCl3 , SOCl2, Cl 2 , can be utilized as
chloride donor.Preferably, the compound of Formula (VI) is provided by
removing the compound of Formula (VII) from the reaction mixture using
liquid-liquid extraction. Some alternatives to chlorination include
bromination and the introduction of OTf, OS0 2 CF 3 , SOPh, SO 2Ph, SO 2 Et or
SOEt etc. to set up a good leaving group for following SNAr reaction.
Scheme 3
0 ci R2 WR
Z: u NH Chlorination
(V11) (VI)
[0036] The chlorination reactions with different solvents and reaction
conditions were investigated for the efficient production of 5 (Table 3). Completion of
the reaction was monitored using HPLC, both by monitoring the disappearance of the
reactant 4 and the formation of the product 5. The purity of the product was
influenced both by the reaction solvent and reaction's batch size. The crude product 5
was directly used in the next step (SNAr reaction) after workup, as it was not stable on
isolation.
Table 3
HPLC(%)
Entry 4 (g) Temp (°C) solvent Time (h) 5 Impurities
1 0.7 70 toluene 2.0 77.4 19.2
2 5.0 65 CH 3CN 2.0 93.9 2.7
3 20.0 65 CH 3CN 1.5 94.1 3.0
4 108.0 70 CH 3CN 1.5 90.2 5.4
5 164.0 80 CH 3CN 8.0 96.7 2.1
Example 4
Preparation of the compound of Formula (IV) by SNAr reaction
[0037] A compound of Formula (IV) can be obtained by SNAr reaction
of the compound of Formula (VI) with a compound of Formula (V) (Scheme
4); wherein B is an arylene or heteroarylene; W and Z is, independently, N or CRa, Ra
being hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, hetrocycloalkenyl alkoxy, halogen, alkoxy amino, or
alkoxy alkylamino group; R 1 and R2 is, independently, being hydrogen, halogen, or
OA, wherein R 1 and R2 are not both hydrogens; A is an alkylamino group; n is 0, 1, 2,
3, or 4. Preferably, the compound of Formula (IV) is provided as solid by
centrifugation.
HN BNHBoc ci 2 1-$' HN nB BB C NHBoc R2W R2W N(V) R2 W R R1 Z Base, solvent R1 Z N (VI) (IV)
[0038] Different types of bases and solvent conditions were tested for the
SNAr displacement reaction of 5 with 6 (Table 4). There was a need to remove the
-3% level of impurity present in the final product. The use of a mixture of
EtOAc/MeOH (10:1.5) solvent to wash the product 7 removed the impurity
successfully.
Table 4
HPLC(%)
Entry 5 (g) base solvent Temp (C) Time (h) 7 Impurities
1 0.60 Et3N i-PrOH 80 2.5 83.0 8.9
2 0.60 Et3N EtOH 80 2.5 83.3 8.0
3 5.00 K2 C0 3 DMF 70 2.0 72.4 9.7
4 3.30 K2 C0 3 DMAC 70 2.5 75.1 12.2
5 3.34 DIPEA i-PrOH 80 3.0 79.1 11.3
6 0.50 DIPEA EtOH 80 2.0 68.3 16.5
7 1.20 DIPEA CH 3CN 65 7.0 96.4 3.5
8 517.30 DIPEA CH 3CN 65 9.0 95.0 3.3
[0039] tert-Butyl(5-(2-((7-(3-(dimethylamino)propoxy)-quinazolin-4
yl)amino)ethy)thiazo-2-yl) Carbamate(7). 1H-NMR (400 MHz, DMSO-d6 ) 6 11.16
(brs, 2H), 8.41 (s, 1H), 8.24 (t, J= 5.2 Hz, 1H), 8.10 (d, J= 9.2 Hz, 1H), 7.11 (dd, J=
9.2, 2.4 Hz, 2H), 7.07 (dd, J= 8.4, 2.4 Hz, 2H), 4.12 (t, J= 6.4 Hz, 2H), 3.70 (q, J=
12.8, 6.8 Hz, 2H), 3.06 (t, J= 6.8 Hz, 2H), 2.38 (t, J= 7.2 Hz, 2H), 2.15 (s, 6H), 1.92
1.85 (in, 2H), 1.44 (s, 9H). 13 C-NMR (100 MHz, DMSO-d 6 ) 6 161.7,158.9,158.3,
155.5, 152.7, 151.3, 134.9, 128.3, 124.2, 116.9, 109.1, 107.4, 80.8, 66.1, 55.5, 45.1,
41.7, 27.8, 26.6, 25.7. HRMS (ESI) calcd for C 2 3H 3 2N6 NaO 3 S [M + Na]: 495.2154;
found 495.2679.
Example 5
Removing Boc group to obtain the compound of Formula (II)
[0040] The compound of Formula (II) can be obtained by removing
the Boc protective group from a compound of Formula (IV) in acidic
condition (Scheme 5); wherein B is an arylene or heteroarylene; W and Z is,
independently, N or CRa, Ra being hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetrocycloalkenyl alkoxy, halogen, alkoxy amino, or alkoxy alkylamino group; R1 and R2 is, independently, being hydrogen, halogen, or -OA, wherein R' and R2 are not both hydrogens; A is an alkylamino group; n is 0, 1, 2, 3, or 4. Preferably, the compound of Formula (II) is recrystallized from solvents.
Scheme 5
HNHNMn B BNHBoc HN HN BNH2 n B 2 R 2 W N Acid, solvent R W
R1 R' Z N
(IV) (II)
[0041] The synthesis of intermediate 8 was taken as an example. To obtain
high purity on a bulk scale, compound 7 was reacted with TFA in dichloromethane at
around 40-45 °C to remove the Boc protective group to get 8 as TFA salt. The pure
product's isolation from the reaction mixture required a robust recrystallization
procedure, for which MTBE (methyl tert-butyl ether) and MeOH solvent mixture was
used. Consequently, using the above reaction and workup method, intermediate 8 was
obtained in an excellent yield (99%) and HPLC purity (98.2%) without the need for
column purification.
[0042] 5-(2-((7-(3-(Dimethylamino)propoxy)quinazolin-4
yl)amino)ethyl)thiazol-2-amine (8). 1HNMR (400 MHz, DMSO-d) 6 9.98 (brs, 1H),
9.83 (brs, 1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.38 (d, J= 9.6 Hz, 1H), 7.40 (dd, J= 9.2,
2.4 Hz, 1H), 7.25 (d, J= 2.4 Hz, 1H), 7.04 (s, 1H), 4.24 (t, J= 6.0 Hz, 2H), 3.86 (q, J
= 12.4, 6.4 Hz, 2H), 3.25 (brs, 2H), 3.03 (t, J= 6.4 Hz, 2H), 2.83 (s, 6H), 2.22-2.15
(in, 2H). "C-NMR (100 MHz, DMSO-d), 6 169.6, 163.6, 160.1, 158.9 (q, J= 64.9,
32.8 Hz, C=O, trifluoroacetic acid), 151.4, 140.2, 125.7 (d, J= 98.4 Hz), 121.4 (CF 3 , trifluoroacetic acid), 118.4 (d, J= 31.3 Hz), 115.3, 106.9, 101.2, 65.9, 53.9, 42.2,
41.8,25.5,23.6. HRMS (ESI) called for Ci8 H2 5N 6 0S [M+H]: 373.1810; found
373.1807.
Example 6
Urea bond formation to provide the compound of Formula (I)
[0043] The compound of Formula (I) can be obtained by reacting a
compound of Formula (III) with a compound of Formula (II) in basic
condition (Scheme 6); wherein B is an arylene or heteroarylene; D is an alkyl,
alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, or hetrocycloalkenyl group; W and Z is, independently, N or CRa,
Ra being hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, hetrocycloalkenyl alkoxy, halogen, alkoxy amino, or
alkoxy alkylamino group; R 1 and R2 is, independently, being hydrogen, halogen or
OA, wherein R 1 and R2 are not both hydrogens; A is an alkylamino group; n is 0, 1, 2,
3, or 4. Preferably, the compound of Formula (I) is recrystallized from
solvents.
Scheme 6 {$~.NH 2 H H HN B, O=C=N-D HN B NND R2 W (III) R2 W N Z:: N R Z N Base, solvent R Z N,
(II) (I)
[0044] As an example, the compound 10 was synthesized using the coupling
reaction, where the reaction between intermediate 8 and 3-chlorophenyl isocyanate
(9) was carried out in DCM using Et3N as a base. Solvent systems were screening to
carry out the urea bond formation (Table 5). The reaction in CH2C2/CH3CN (1:1)
solvent mixture went on to completion with a good yield of the compound 10, which
was isolated by recrystallization from a mixture of CH 3CN and MeOH (1:1). The
CH 2C 2/CH 3CN (1:1) solvent system avoided sticky gel formation during the reaction
process. Moreover, it was found that the starting material's moisture content needs to
be kept at a minimum so that 8 could be consumed completely during the reaction to
get the compound 10 in high purity.
Table 5
10
Entry 8 (g) Solvent Time (h) Yield (%) Purity(%)
1 10.0 CH2 Cl 2 12 65.2 89.4
2 10.0 CH2Cl 2/MeOH 12 66.0 96.5
3 16.6 CH2Cl 2/CH 3CN 5 69.3 96.9
4 130.0 CH2Cl 2/CH 3CN 5 92.9 97.7
[0045] J-(3-Chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)
propoxy)quinazolin-4-yl)amino)ethyl)thiazol-2-yl)urea(10). 1H-NMR (400 MHz,
DMSO-d) 6 10.64 (brs, 1H), 9.20 (brs, 1H), 8.41 (s, 1H), 8.25 (t, J= 5.6 Hz, 1H),
8.11 (d, J = 9.2 Hz, 1H), 7.70 (s, 1H), 7.33-7.28 (in, 2H), 7.11 (dd, J= 9.2, 3.2 Hz,
2H), 7.05 (in, 2H), 4.12 (t, J= 6.4 Hz, 2H), 3.72 (q, J= 12.8, 6.8 Hz, 2H), 3.07 (t, J=
7.2 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.15 (s, 6H), 1.92-1.85 (in,2H). 13C-NMR (100
MHz, DMSO-d) 6 161.7, 159.2, 158.9, 155.6, 152.5, 151.3, 140.5, 133.2, 132.7,
130.4, 127.3, 124.2, 122.0, 117.8, 116.9, 109.1, 107.4, 66.0, 55.5, 45.1, 41.6, 26.6,
25.8. HRMS (ESI) calcd for C2 5H28ClN7NaO2S [M + Na]: 548.1611; found 548.1598.
Example 7
Kilogram-scale total synthesis of the compound of Formula (I)
[0046] Herein, it is demonstrated a practical and scale-up procedure that can
operate on a 3 kg scale for the production of compound 10. The optimized process
manufacturing was run on a multikilogram scale in a kilo lab facility using a six-step
reaction sequence. All the steps provided the product as solid and were centrifugation
either from the reaction mixture directly or recrystallized from solvents to get the
product in high purity.
[0047] A 200.0 L glass-lined jacketed reactor was charged with ethanol (70.0
kg) and 2-amino-4-fluorobenzoic acid (1) (9.70 Kg, 62.52 mol, 1.0 equiv). The
resulting mixture was stirred at room temperature and then added formamidine acetate
(13.13 kg, 125.04 mol, 2.0 equiv) in one portion at the same temperature. The reaction
mixture was warmed to reflux and stirred for 2 days. When the HPLC analysis
indicated <4% of the starting material 1 remained, the batch temperature was
gradually decreased to 10-15 °C °Cand stirred for 4 h at that temperature. While
maintaining the internal temperature of 10-15 °C, the compound was precipitated, the
mixture was centrifuged, and the cake was rinsed with ethanol (8.0 Kg). The wet cake
was dried in an oven under vacuum at 55 °C for 24 h to afford compound 2 (9.17 kg,
89.4%) as an off-white solid with an HPLC purity of 99.8%.
[0048] Another 200.0 L glass-lined jacketed reactor was charged with 3
(dimethylamino)propan-1-ol (3) (31.62 kg, 306.59 mol, 5.5 equiv) and powdered
KOH (12.51 kg, 222.98 mol, 4.0 equiv). The resulting mixture was warmed to 120 °C
and stirred for 1 h. Then, quinazolinone 2 (9.15 kg, 55.75 mol, 1.0 equiv) was added
to the reactor at that temperature. The reaction mixture was stirred at the same temperature for 8 h; 1PLC analysis indicated only 0.3% of 2 remained (Rt = 6.9 min).
The reaction mixture was cooled down to 15 °C, and H20 (100.0 L) was added to the
reactor dropwise over a 1 h period while maintaining the internal temperature at 20-25
°C. The resulting mixture was continuously extracted with EtOAc (650.0 kg) for 3
days using a liquid-liquid continuous extractor (Reddy et. al., Org. Process Res. Dev.
2021, 25, 817-830). Finally, the aqueous phase was extracted twice with a mixture of
EtOAc (150.0 kg x 2) and EtOH (10.0 kg x 2); the combined organic phase was
concentrated under vacuum at 50 °C until the volume was about 55.0 L. The mixture
was treated with EtOH (5.0 kg) and heated to 45 °C for 1 h. The solution temperature
was decreased to 15 °C and held for about 2 h to afford the product's precipitation.
The mixture was centrifuged, collected the solid, and the cake rinsed with a mixture
of EtOAc (4.9 kg) and EtOH (0.46 kg), which gave 11.20 kg wet cake. The wet cake
was dried in an oven under vacuum at 45 °C for 18 h to give the desired product 4
(9.22 kg, 66.9%) as a white solid, with an HPLC purity of 98.5%.
[0049] A 50.0 L glass-lined jacketed reactor was charged with CH 3CN (7.8
kg) and 4 (1.64 kg, 6.63 mol, 1.0 equiv) and stirred at room temperature. Further,
POCl3 (2.03 kg, 13.26 mol, 2.0 equiv) was added into the reaction mixture over 10
min while maintaining the batch temperature below 30 °C. The temperature was
increased to -80 °C over 45 min (the reaction mixture cleared at 56 C) and held for 8
h. The completion of the reaction was established by HPLC analysis, which indicated
that the unreacted starting material was around 1%. The reaction was cooled to-~35
°C over 1 h, charged with CH 2Cl 2 (46.0 kg), and then transferred into a dropping tank.
The mixture in the dropping tank was transferred into a 12.5% K2HPO 4 aqueous
quench solution (97.4 kg) in a 200.0 L reactor over a 20 min period while maintaining
the temperature -5 to +5 °C to reach the target pH 4-5. Then, 50% K 2C03 aqueous
solution (14.8 kg) was charged into the reactor over 20 min at 5-15 °C until pH 9-10.
The mixture was stirred for 20 min at about 15 °C and settled to split layers. The
organic layer was separated, and the aqueous layer was washed with CH2Cl2 (46.0 kg)
again. The combined organic phase was washed with 5% brine (33.0 kg) and dried
over Na2SO4 (6.6 kg) for 2 h. The mixture was filtered and rinsed with CH 2C12 (13.0
kg), the filtrate was sampled for HPLC purity and found to be 96.7%. Due to the
instability of chloro compound 5, the above filtrate was directly used for the next step.
[0050] The amine 6 (1.45 kg, 5.97 mol, 0.9 equiv) was directly charged into
the filtrate 5, which was obtained in the earlier step. The reaction mixture was then
concentrated under vacuum at 20 °C to about 2.5 L volume and was charged with
CH 3CN (8.2 kg) and then concentrated to about 4.1 L volume. The mixture was
transferred to a 50.0 L reactor, and CH 3CN (6.6 kg) and DIPEA (0.856 kg, 6.63 mol,
1.0 equiv) were charged into the reactor. The mixture was heated to 55 °C and held for
2 h; then the batch temperature raised to 65 °C over 30 min and held for 2 h with
stirring. An additional amount of amine 6 (0.161 kg, 0.663 mol, 0.1) was charged into
the reactor at that temperature. The reaction temperature was raised to 75 °C and
stirred for 4 h. The reaction mixture was sampled by HPLC, which detected 3.5%
unreacted starting material 5. Then, MeOH (0.62 L) was added into the reactor while
the temperature was maintained at about 65 °C and held for 1 h. The mixture was
cooled to 20 °C over 2 h. The mixture was stirred for about 5 h and then centrifuged
to get the crude cake and washed with a mixture of CH 3CN (7.0 kg) and MeOH (0.40
kg) to get 4.56 kg 7 as a wet-cake with 89.5% HPLC purity. A solution of EtOAc
(6.32 kg) and MeOH (1.26 kg) and the wet cake 4.56 kg in a 50 L reactor was heated
to 85 °C for 12 h. Then, the reaction temperature cooled to 20 °C over 2.5 h and held
for 3 h. The mixture was centrifuged, and the cake was rinsed with EtOAc (4.0 kg) to
afford a 1.30 kg product. The wet cake was dried in an oven under vacuum at 50 °C
for 10 h to get the product 7 (1.22 kg, 38.9% yield over two steps) as a light brown solid with 96.8% HPLC purity.
[0051] A 100.0 Ljacketed reactor was flushed with nitrogen and charged with
Boc-amine 7 (4.00 kg, 8.46 mol, 1.0 equiv) and CH2 Cl2 (42.2 kg). Trifluoroacetic acid
(15.20 kg, 132.88 mol, 15.7 equiv) was dropwise added into the reactor over a period
of 1 h, while the reaction temperature was maintained <30 °C. The resultant mixture
was heated to 45 °C and stirred at that temperature for about 6 h. When the HPLC
analysis indicated that <1% of 7 remained, then, the reaction was concentrated to
about 10.0 L volume. Subsequently, MeOH (3.2 kg) and MTBE (12.0 kg) were
charged into the reactor and stirred at room temperature for about 6 h. The mixture
was filtered, and the solid obtained was washed with MTBE (12.0 kg). The wet cake
was dried in a vacuum oven at 50 °C for about 2 days to yield 5.85 kg (-99%) of 8 as
a white solid with 98.2% HPLC purity.
[0052] A 200.0 L jacketed reactor flushed with nitrogen was charged with 8
(5.57 kg, 8.05 mol, 1.0 equiv), CH 2 Cl2 (61.0 kg), and dry CH 3CN (36.8 kg) while
stirring at 32 °C. Then, Et3 N (2.80 kg, 27.60 mol, 3.43 equiv) was added at that
temperature over 15 min and stirred for 10 min. Next, 3-chlorophenyl isocyanate
(2.06 kg, 13.44 mol, 1.67 equiv) was added at that temperature over 5 min, and the
mixture was stirred for about 4 h while the temperature was maintained at about 35
°C; HPLC analysis determined that <0.07% of the starting material 8 remained
unreacted. The reaction was cooled to 25 °C, held for 1 h, and then centrifuged to
obtain the product as a cake, which was recrystallized with a CH 3CN (46.0 kg) and
MeOH (36.8 kg) solvent mixture. The wet cake was dried in an oven under vacuum at
°C for over 12 h to afford the final product 10 (3.04 kg, 71.8%) as a white solid
with purity of 97.8% and 97.2% assay purity with a single maximum impurity of
-0.6-0.7%.
[0053] While a number of embodiments of this invention have be described, it
is apparent that our basic examples may be altered to provide other embodiments that
utilize the compounds and methods of this invention. Therefore, it will be appreciated
that the scope of this invention is to be defined by the appended claims rather than by
the specific embodiments that have been represented by way of example.

Claims (18)

  1. CLAIMS 1. A process for preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, H H HN B N D R W 0 N Ri Z N
    (I) wherein B is an arylene or heteroarylene; D is an alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or hetrocycloalkenyl group; W and Z is, independently, N or CRa, Ra being hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetrocycloalkenyl alkoxy, halogen, alkoxy amino, or alkoxy alkylamino group;
    R 1 and R 2 is, independently, being hydrogen, halogen, or , wherein R and R2 are not both hydrogens; A is an alkylamino group; n is 0, 1, 2, 3, or 4; and the process comprising: reacting a compound of Formula (VIII) with a alkanolamine to form a compound of Formula (VII); wherein X and Y is, independently, being a halogen or hydrogen, X and Y are not both hydrogens; converting a compound of Formula (VII) to the compound of Formula (VI); reacting a compound of Formula (V) with a compound of Formula (VI) to form a compound of Formula (IV); converting a compound of Formula (IV) to the compound of Formula (III); andreacting a compound of Formula (II) with a compound of Formula (III) 14{' NH 2 HN nB R2 W
    O=C=N-D R1 Z N
    (II) (III)
    HN B,NHBoc
    2N BNHBoc R1 Z: NH
    (IV) (V)
    C1 0
    RI>RN N R2 X Z NH
    (VI) (VII)
    0
    'H Y 1W NH
    (VIII).
  2. 2. The process of claim 1, wherein the alkanolamine is a compound of Formula (IX) A-OH
    (IX).
  3. 3. The process of claim 1, further comprising: reacting a compound of Formula (X) with formamidine acetate to form a compound of Formula (VIII) 0
    W O Y OH X I~Z NH 2
    (X).
  4. 4. The process of claim 2, wherein A is NRbR
    wherein Rband Rc is, independently, hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or hetrocycloalkenyl group; m is 2, 3, or 4.
  5. 5. The process of claim 4, wherein m is 3 and, each R and R is methyl group.
  6. 6. The process of claim 1, wherein R 2 is hydrogen.
  7. 7. The process of claim 1, wherein B is phenyl or thiazolyl group.
    N
  8. 8. The process of claim 7, wherein B is XS
  9. 9. The process of claim 1, wherein D is 6-membered aryl or heteroaryl group.
  10. 10. The process of claim 9, wherein D is C, , OMe
    MeO CI, or C1.
    _N
  11. 11. The process of claim 1, wherein R2 is hydrogen, A is NRbR, B is 8 ,D
    is cl, each W, and Z is CR, Ra is hydrogen, n is 2, m is 3, and each R and R is methyl group.
  12. 12. The process of claim 1, wherein the compound of Formula (I) is recrystallized from solvents.
  13. 13. The process of claim 1, wherein the compound of Formula (III) is recrystallized from solvents.
  14. 14. The process of claim 1, wherein the compound of Formula (IV) is provided as solid by centrifugation.
  15. 15. The process of claim 1, wherein the compound of Formula (VI) is provided by removing the compound of Formula (VII) from the mixture thereof using liquid-liquid extraction.
  16. 16. The process of claim 15, wherein the liquid-liquid extraction is conducted by adding ETOAc to the mixture and collecting the compound of Formula (VI) therein.
  17. 17. The process of claim 1, wherein the compound of Formula (VII) is provided as solid by centrifugation.
  18. 18. The process of claim 3, wherein the compound of Formula (VIII) is provided as solid by centrifugation.
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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LEE, KUN-HUNG. Et al. "Discovery of BPR1R024, an orally active and selective CSF1R inhibitor that exhibits antitumor and immunomodulatory activity in a murine colon tumor model", Journal of Medicinal Chemistry, 2021, 64, 14477-14497. *
LIN, SHU-YU. Et al. "Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors", Bioorganic Chemistry, 2020, 98, 103689 (13 pages). *
REDDY, J. S. et al. "Development of a robust scale-up synthetic route for BPR1K871: A clinical candidate for the treatment of acute myeloid leukemia and solid tumors", Organic Process Research & Development, 2021, 25, 817-830 *

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