AU2021404731B2 - Synthesis method for cyclopropyl-containing chiral amine hydrochloride - Google Patents
Synthesis method for cyclopropyl-containing chiral amine hydrochloride Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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Abstract
The present invention relates to the field of synthesis and preparation of medical intermediates. Disclosed is a synthesis method for a medical intermediate cyclopropyl-containing chiral amine hydrochloride. According to the present invention, a compound (I) cycloprogyl dehyde is used as an initial raw material, and a target product chiral amine hydrochloride is obtained by means of condensation, alkylation, debenzylation, chiral resolution and salification reactions. The synthesis method for the medical intermediate cyclopropyl-containing chiral amine hydrochloride in the present invention has the characteristics of low cost and simple operation.
Description
Description
The present invention relates to the technical field of the synthesis of
pharmaceutical and organic chemical intermediates, in particular to a method for
synthesizing cyclopropyl-containing chiral amine hydrochloride.
Cyclopropyl-containing chiral amines are a widely applied important class of
pharmaceutical intermediates. For example, they can be used to synthesize
corticotropin releasing factor-i (CRF1) receptor antagonist as reported in an article (J.
Med. Chem. 2009, 52, 4173), synthesize quinazoline drugs for the treatment of cancer
as reported in another article (ACS Med. Chem. Lett. 2018, 9, 9, 941-946), synthesize
Cathepsin S inhibitors for the treatment of autoimmunity and relevant diseases as
reported in a patent (W02011109470), and synthesize and regulate Ras activators for
the treatment of cancer as reported in another patent (W2018212774). Generally,
cyclopropyl-containing chiral amines have been widely applied in the field of
pharmaceutical synthesis, with great value in developing relevant synthesis processes.
A difficulty of synthesizing cyclopropyl-containing chiral amine compounds is
the formation of chiral amine structures. There are usually two synthesis strategies
described in the following literature review:
For the first method, as reported in a patent (J. Med. Chem. 2009, 52, 4173) and
other references, the target product is generated from
N-methoxy-N-methyl-2-methoxyacetamide as the raw material through
cyclopropanation, reductive amination, Cbz protection, chiral resolution and
deprotection reactions. In this route, a long 5-step reaction route is required; the raw
material is expensive; an HPLC chiral column is required for chiral resolution, which
cannot be scaled up for industrialization; a large amount of sodium
triacetylborohydride is used for reductive amination, which is not suitable for
Description
industrial production due to a high risk of explosion. N0
NON R R N bz 0 -h
' R 3 R NHCbz NH 2 ' HCI
For the other method, as reported in an article (A CS Med. Chem. Lett. 2018, 9, 9,
941-946), cyclopropanecarboxaldehyde as the raw material is first condensed with
chiral tert-butylsulfinamide, then alkylated with a Grignard reagent, and finally
deprotected from the tert-butylsulfinyl group to obtain the product. In this route, chiral
tert-butylsulfinamide used is expensive and produces unpleasant gases, and the
multi-step reaction involves column purification operations, which is not suitable for
industrial production.
0 + H 2N' H H (s)A)
HN-S (R) NH2
The existing synthesis routes all have shortcomings, such as long routes with
multiple steps, the need to use expensive reagents, involvement of flammable and
explosive hazardous reagents or production processes, the need for special production
equipment, and serious environmental pollution, which are disadvantageous to
industrial mass production. Therefore, there is a demand for a method for preparing
cyclopropyl-containing chiral amines, which is featured by simple reaction, low cost
and easy industrial production.
Description
The technical problem to be solved by the present invention is to develop a
method for synthesizing cyclopropyl-containing chiral amine hydrochloride, which is
featured by available raw material, high yield, good quality, simple operations, and
suitability for industrial production.
In order to realize the aforesaid purpose, the present invention adopts the
following technical solution:
The specific synthesis process is as follows:
Cyclopropanecarboxaldehyde (compound (I)) as the starting material is
condensed with (R)-1-phenylethylamine to prepare a compound (II), alkylated with
the corresponding Grignard reagent to prepare a general formula compound (III),
deprotected through hydrodebenzylation to obtain a general formula compound (IV),
and prepared a general formula compound product (V) by chiral resolution and
salification.
SN HN >--I-+ H H R
II Ill
NH 2 NH 2 - • HCI R R
IV V A method for synthesizing cyclopropyl-containing chiral amine hydrochloride
includes the following synthesis steps:
1) condensing cyclopropanecarboxaldehyde (compound (I)) as the starting
material with (R)-1-phenylethylamine to prepare a compound (II), and reacting the
compound (I) with (R)-1-phenylethylamine in a solvent at 50-110°C to obtain the
compound (II) or its solution through workup, wherein the solvent is any one or more
of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane
Description
and dichloromethane; the molar ratio of cyclopropanecarboxaldehyde and
(R)-1-phenylethylamine is 1:1-3;
2) reacting the compound (II) solution with a Grignard reagent solution at
-50-100°C to obtain a general formula compound (III) or its solution through workup,
wherein the molar ratio of the compound (II) and the Grignard reagent is 1:1-10;
3) catalyzing the general formula compound (III) solution with a catalyst for a
reaction at 0-100°C under a 0-10 MPa hydrogen atmosphere to prepare a general
formula compound (IV) or its solution through workup;
4) resolving the general formula compound (IV) or its solution by adding a
resolution reagent and a solvent, and converting it into hydrochloride through workup
to prepare a general formula compound (V), wherein the resolution reagent is any one
or more of (S)-mandelic acid, (S)-acetylmandelic acid, L-dibenzoyltartaric acid and
L-tartaric acid; the solvent is any one or more of methanol, ethanol, isopropanol,
n-propanol, n-butanol, isobutanol, tert-butanol and water; the molar ratio of the
compound (IV) and the resolution reagent is 1:0.5-10;
As a further preferred embodiment, in step 1), the molar ratio of
cyclopropanecarboxaldehyde and (R)-1-phenylethylamine is 1:1-1.5, the solvent is
toluene, the reaction temperature is 80-110 °C , and the compound (II) is prepared
through a reaction.
As a further preferred embodiment, in step 1), the compound (II) or its solution is
prepared through workup for a reaction in the next step.
As a further preferred embodiment, in step 2), the reaction temperature is
-20-60 °C , and the molar ratio of the compound (II) and the Grignard reagent is
1:1-1.5.
As a further preferred embodiment, the Grignard reagent is methylmagnesium
chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium
bromide, vinylmagnesium chloride, vinylmagnesium bromide, ethynylmagnesium
chloride, ethynylmagnesium bromide, n-propylmagnesium chloride, n-propylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium
bromide, n-butylmagnesium chloride, n-butylmagnesium bromide,
Description
isobutylmagnesium chloride, isobutylmagnesium bromide, tert-butylmagnesium
chloride or tert-butylmagnesium bromide; the corresponding R group is methyl, ethyl,
vinyl, ethynyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
As a further preferred embodiment, in step 2), the general formula compound (III)
or its solution is prepared through workup for a reaction in the next step.
As a further preferred embodiment, in step 3), the reaction temperature is
-60°C, and the hydrogen pressure is 0.5-1 Mpa.
As a further preferred embodiment, the catalyst is any one or more of
palladium-carbon, rhodium-carbon, platinum-carbon and platinum oxide.
As a further preferred embodiment, in step 3), the catalyst is palladium-carbon.
As a further preferred embodiment, in step 4), the resolution reagent is
(S)-mandelic acid, the molar ratio of the general formula compound (IV) and the
resolution reagent is 1:0.8-1.5, the solvent is isopropanol, and the compound (V) is
prepared through conversion into hydrochloride after resolution.
The method for synthesizing cyclopropyl-containing chiral amine hydrochloride
provided by the present invention has the following advantages:
The present invention adopts a relatively simple route and a commercially
available and relatively cheap raw material, and avoids complex special operations,
which is suitable for industrial production; it provides a new solution for synthesizing
and preparing cyclopropyl-containing chiral amine hydrochloride.
To make the purpose, technical solution and advantages of the present invention
clearer, the present invention will be further described below in conjunction with
examples:
Embodiment 1:
Description
NH 2 NH 2 • HCI
IV-1 V-1 Under a nitrogen atmosphere, 70.1 g of cyclopropanecarboxaldehyde (1.0 mol,
1.0 eq) and 127.3 g of (R)-1-phenylethylamine (1.05 mol, 1.05 eq) were added to a
reaction flask and dissolved in 700 g of toluene. The temperature was increased to
-90 °C for a reaction for 12 h, and then decreased to 10-20 °C . 100 g of 0.1 M
hydrochloric acid was added for washing once. 100 g of anhydrous magnesium sulfate
was added to an organic phase. Through drying and filtering, a compound (II) solution
was prepared and directly used for a reaction in the next step.
The compound (II) solution in toluene was cooled to -20 °C . 620 mL of an
ethylmagnesium chloride solution in tetrahydrofuran (1.1 mol, 1.1 eq) was added
dropwise. After stirring for 30 min, an aqueous ammonium chloride solution was
added. Through quenching and separation, the organic phase was washed once with
water. A compound (111-1) solution was prepared and directly used for a reaction in
the next step.
The compound (111-1) solution was put into the autoclave. 5 g of 5% Pd/C was
added. After replacement with hydrogen, the pressure was adjusted to 0.5 MPa for a
reaction for 4 h. Through discharging and filtering, a compound (IV-i) solution was
obtained and used for a reaction in the next step.
152.2 g of (S)-mandelic acid (1.0 mol, 1.0 eq) and 200 mL of isopropanol were
added to the compound (IV-1) solution obtained in the previous step. The temperature
was increased to 70°C for stirring for 2 h, and then decreased to 10-20°C for filtering.
200 mL of isopropanol was added to the filter cake for beating at 20-30°C for 3 h.
After beating, filter to obtain the filter cake. 500 mL of methyl tert-butyl ether and
Description
300 mL of a 5M sodium hydroxide solution were added and stirred for 30 min. The
organic phase was taken through separation. 350 mL of a 4M hydrogen chloride
solution in 1,4-dioxane was added to the organic phase and stirred for 1 h. Through
filtering and drying of the filter cake, 115.7 g of product was obtained. The product is
a white solid, i.e. a compound (V-1), with a yield of 85.3%, purity of 99.5% and an ee
value of 99%. Nuclear magnetic resonance (NMR) data of compounds is as follows: 1H NMR (400 MHz, D 2 0): 62.07 (m, 1H), 61.44 (m, 2H), 60.68 (t, 3H), 60.67 (m,
1H), 60.33 (m, 2H), 60.03 (m, 2H); 1 3 C NMR (400 MHz, D20): 656.6, 624.0, 610.6, 66.9,61.5.
Embodiment 2:
0 N HN
II 111-2
NH 2 NH 2 • HCI
IV-2 V-2 Under a nitrogen atmosphere, 70.1 g of cyclopropanecarboxaldehyde (1.0 mol,
1.0 eq) and 145.5 g of (R)-1-phenylethylamine (1.2 mol, 1.2 eq) were added to a
reaction flask and dissolved in 1,000 g of toluene. The temperature was increased to
-90°C for a reaction for 10 h, and then decreased to 10-20 °C . 200 g of0.1M
hydrochloric acid was added for washing once. 100 g of anhydrous magnesium sulfate
was added to an organic phase. Through drying and filtering, a compound (II) solution
was prepared and directly used for a reaction in the next step.
The compound (II) solution in toluene was cooled to -20 °C . 620 mL of a
vinylmagnesium bromide solution in tetrahydrofuran (1.1 mol, 1.1 eq) was added
dropwise. After stirring for 30 min, an aqueous ammonium chloride solution was
added. Through quenching and separation, the organic phase was washed once with
Description
water. A compound (111-2) solution was prepared and directly used for a reaction in
the next step.
The compound (111-2) solution was put into the autoclave. 3 g of 5% Pd/C was
added. After replacement with hydrogen, the pressure was adjusted to 1.0 MPa for a
reaction for 4 h. Through discharging and filtering, a filtrate as a compound (IV-2)
solution was obtained and used for a reaction in the next step.
137.0 g of (S)-mandelic acid (0.95 mol, 0.95 eq) and 200 mL of isopropanol were
added to the compound (IV-2) solution obtained in the previous step. The temperature
was increased to 70°C for stirring for 2 h, and then decreased to 10-20°C for filtering.
200 mL of isopropanol was added to the filter cake for beating at 20-30°C for 3 h.
After beating, filter to obtain the filter cake. 500 mL of methyl tert-butyl ether and
300 mL of a 5M sodium hydroxide solution were added and stirred for 30 min. The
organic phase was taken through separation. 350 mL of a 4M hydrogen chloride
solution in 1,4-dioxane was added to the organic phase and stirred for 1 h. Through
filtering and drying of the filter cake, 116.8 g of product was obtained. The product is
a white solid, i.e. a compound (V-2), with a yield of 87.4%, purity of 99.8% and an ee
value of 99.1%. Nuclear magnetic resonance (NMR) data of compounds is as follows: 1H NMR (400 MHz, D20): 65.81 (m, 1H), 65.28 (m, 2H), 63.03 (m, 1H), 60.95 (m, 13 1H), 60.43 (m, 4H); C NMR (400 MHz, D 2 0): 6132.5, 6119.4, 658.3, 612.8, 63.3,
62.6.
Embodiment 3:
0 ~HNF H H
11 111-3
NH2 NH 2 • HCI
IV-3 V-3
Description
Under a nitrogen atmosphere, 70.1 g of cyclopropanecarboxaldehyde (1.0 mol,
1.0 eq) and 133.4 g of (R)-1-phenylethylamine (1.1 mol, 1.1 eq) were added to a
reaction flask and dissolved in 1,000 g of toluene. The temperature was increased to
100-105°C for a reaction for 18 h, and then decreased to 10-20°C. 200 g of0.1M
hydrochloric acid was added for washing once. 100 g of anhydrous magnesium sulfate
was added to an organic phase. Through drying and filtering, a compound (II)solution
was prepared and directly used for a reaction in the next step.
The compound (II) solution in toluene was cooled to 20 °C . 620 mL of an
isopropylmagnesium chloride solution in tetrahydrofuran (1.1 mol, 1.1 eq) was added
dropwise. After stirring for 30min, an aqueous ammonium chloride solution was
added. Through quenching and separation, the organic phase was washed once with
water. A compound (111-3) solution was prepared and directly used for a reaction in
the next step.
The compound (111-3) solution was put into the autoclave. 10 g of 5% Pd/C was
added. After replacement with hydrogen, the pressure was adjusted to 1.OMPa for a
reaction for 2 h. Through discharging and filtering, a filtrate as a compound (IV-3)
solution was obtained and used for a reaction in the next step.
155.3 g of (S)-acetylmandelic acid (0.8 mol, 0.8 eq) and 300 mL of isopropanol
were added to the compound (IV-3) solution obtained in the previous step. The
temperature was increased to 70°C for stirring for 2h, and then decreased to 10-20°C
for filtering. 300 mL of isopropanol was added to the filter cake for beating at
-30 °C for 3h. After beating, filter to obtain the filter cake. 500 mL of methyl
tert-butyl ether and 300 mL of a 5M sodium hydroxide solution were added and
stirred for 30 min. The organic phase was taken through separation. 350 mL of 4M
hydrogen chloride solution in 1,4-dioxane was added to the organic phase and stirred
for 1 h. Through filtering and drying of the filter cake, 125.3 g of product was
obtained. The product is a white solid, i.e. a compound (V-3), with a yield of 83.7%,
purity of 99.6% and an ee value of 99.0%. Nuclear magnetic resonance (NMR) data
of compounds is as follows: IH NMR (400 MHz, D 2 0): 62.0 (m, 1H), 61.74 (m, 1H),
Description
60.74 (d, 6H), 60.67 (m, 1H), 60.23 (m, 4H); 13 C NMR (400 MHz, D 2 0): 661.2, 629.5,
615.7, 69.0, 63.0.
Embodiment 4:
II 111-4
NH 2 NH 2 HCI
IV-4 V-4
Under a nitrogen atmosphere, 70.1 g of cyclopropanecarboxaldehyde (1.0 mol,
1.0 eq) and 133.4 g of (R)-1-phenylethylamine (1.1 mol, 1.1 eq) were added to a
reaction flask and dissolved in 1,000 g of toluene. The temperature was increased to
100-105°C for a reaction for 18h, and then decreased to 10-20°C. 200 g of0.1M
hydrochloric acid was added for washing once. 100 g of anhydrous magnesium sulfate
was added to an organic phase. Through drying and filtering, a compound (II) solution
was prepared and directly used for a reaction in the next step.
The compound (II) solution in toluene was cooled to 40 °C . 620 mL of an
ethynylmagnesium chloride solution in tetrahydrofuran (1.1 mol, 1.1 eq) was added
dropwise. After stirring for 30min, an aqueous ammonium chloride solution was
added. Through quenching and separation, the organic phase was washed once with
water. A compound (111-4) solution was prepared and directly used for a reaction in
the next step.
The compound (111-4) solution was put into the autoclave. 2 g of 5% Pd/C was
added. After replacement with hydrogen, the pressure was adjusted to 0.2 MPa for a
reaction for 10 h. Through discharging and filtering, a filtrate as a compound (IV-4)
solution was obtained and used for a reaction in the next step.
Description
358.3 g of L-dibenzoyltartaric acid (1.0 mol, 1.0 eq) and 300 mL of isopropanol
were added to the compound (IV-4) solution obtained in the previous step. The
temperature was increased to 70°C for stirring for 2 h, and then decreased to 10-20°C
for filtering. 500 mL of isopropanol was added to the filter cake for beating at
-30°C for 3 h. After beating, filter to obtain the filter cake. 500 mL of methyl
tert-butyl ether and 300 mL of a 5M sodium hydroxide solution were added and
stirred for 30 min. The organic phase was taken through separation. 350 mL of 4M
hydrogen chloride solution in 1,4-dioxane was added to the organic phase and stirred
for 1 h. Through filtering and drying of the filter cake, 106.2 g of product was
obtained. The product is a white solid, i.e. a compound (V-4), with a yield of 80.7%,
purity of 99.5% and an ee value of 99.2%. Nuclear magnetic resonance (NMR) data
of compounds is as follows: 1H NMR (400 MHz, D20): 63.79 (m, 1H), 62.85 (s,
1H), 61.14 (m, 1H), 60.51 (m, 4H); 13 C NMR (400 MHz, D 2 0): 674.7, 674.2, 644.7,
610.6, 61.6.
Embodiment 5:
11 111-5
NH2 NH 2 CHI
IV-5 V-5
Under a nitrogen atmosphere, 70.1 g of cyclopropanecarboxaldehyde (1.0 mol,
1.0 eq) and 133.4 g of (R)-1-phenylethylamine (1.1 mol, 1.1 eq) were added to a
reaction flask and dissolved in 1,000 g of toluene. The temperature was increased to
100-105°C for a reaction for 18 h, and then decreased to 10-20°C. 200 g of0.1M
hydrochloric acid was added for washing once. 100 g of anhydrous magnesium sulfate
Description
was added to an organic phase. Through drying and filtering, a compound (II)solution
was prepared and directly used for a reaction in the next step.
The compound (II) solution in toluene was cooled to 60 °C . 667 mL of an
n-butylmagnesium bromide solution in tetrahydrofuran (1.2 mol, 1.2 eq) was added
dropwise. After stirring for 30 min, an aqueous ammonium chloride solution was
added. Through quenching and separation, the organic phase was washed once with
water. A compound (111-5) solution was prepared and directly used for a reaction in
the next step.
The compound (111-5) solution was put into the autoclave. 2 g of 5% Pd/C was
added. After replacement with hydrogen, the pressure was adjusted to 0.2 MPa for a
reaction for 10 h. Through discharging and filtering, a filtrate as a compound (IV-5)
solution was obtained and used for a reaction in the next step.
228.3 g of (S)-mandelic acid (1.5 mol, 1.5 eq) and 300 mL of isopropanol were
added to the compound (IV-4) solution obtained in the previous step. The temperature
was increased to 70°C for stirring for 2h, and then decreased to 10-20°C forfiltering.
500 mL of isopropanol was added to the filter cake for beating at 20-30°C for 3 h.
After beating, filter to obtain the filter cake. 500 mL of methyl tert-butyl ether and
300 mL of 5M sodium hydroxide solution were added and stirred for 30 min. The
organic phase was taken through separation. 350 mL of 4M hydrogen chloride
solution in 1,4-dioxane was added to the organic phase and stirred for 1h. Through
filtering and drying of the filter cake, 144.4 g of product was obtained. The product is
a white solid, i.e. a compound (V-5), with a yield of 88.2%, purity of 99.2% and an ee
value of 9 9 .3%. Nuclear magnetic resonance (NMR) data of compounds is as follows: 1H NMR (400 MHz, D20): 62.1 (m, 1H), 61.54 (m, 2H), 61.32 (m, 2H), 61.27 (m,
2H), 60.74 (t, 3H), 60.67 (m, 1H), 60.28 (m, 4H);1 3 C NMR (400 MHz, D 2 0): 659.8,
630.5, 627.7, 622.5, 615.7, 612.8, 62.8.
The foregoing are only preferred embodiments of the present invention and do
not limit the patent scope of the present invention. All equivalent transformations
made by means of the present invention fall within the patent protection scope of the
present invention.
Claims (10)
1. A method for synthesizing cyclopropyl-containing chiral amine hydrochloride,
comprising the following synthesis steps:
1) condensing cyclopropanecarboxaldehyde (compound (I)) as the starting
material with (R)-1-phenylethylamine to prepare a compound (II), and reacting the
compound (I) with (R)-1-phenylethylamine in a solvent at 50-110°C to obtain the
compound (II) or its solution through workup, wherein the solvent is any one or
more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether,
dioxane and dichloromethane; the molar ratio of cyclopropanecarboxaldehyde and
(R)-1-phenylethylamine is 1:1-3;
2) reacting the compound (II) solution with a Grignard reagent solution at
-50-100°C to obtain a general formula compound (III) or its solution through
workup, wherein the molar ratio of the compound (II) and the Grignard reagent is
1:1-10;
3) catalyzing the general formula compound (III) solution with a catalyst for a
reaction at 0-100°C under a 0-10 MPa hydrogen atmosphere to prepare a general
formula compound (IV) or its solution through workup;
4) resolving the general formula compound (IV) or its solution by adding a
resolution reagent and a solvent, and converting it into hydrochloride through
workup to prepare a general formula compound (V), wherein the resolution
reagent is any one or more of (S)-mandelic acid, (S)-acetylmandelic acid,
L-dibenzoyltartaric acid and L-tartaric acid; the solvent is any one or more of
methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol and
water; the molar ratio of the compound (IV) and the resolution reagent is 1:0.5-10;
Claims
0 N HN
H H R I II III
NH 2 NH 2 • HCI R R
IV V 2. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride of claim 1, wherein, in step 1), the molar ratio of cyclopropanecarboxaldehyde and (R)-1-phenylethylamine is 1:1-1.5, the solvent is toluene, the reaction temperature is 80-110°C, and the compound (II) is prepared through a reaction. 3. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride of claim 1, wherein, in step 1), the compound (II) or its solution is prepared through workup for a reaction in the next step. 4. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride of claim 1, wherein, in step 2), the reaction temperature is -20-60°C, and the molar ratio of the compound (II) and the Grignard reagent is 1:1-1.5.
5. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride of claim 1, wherein the Grignard reagent is methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, vinylmagnesium chloride, vinylmagnesium bromide, ethynylmagnesium chloride, ethynylmagnesium bromide, n-propylmagnesium chloride, n-propylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium bromide, n-butylmagnesium chloride, n-butylmagnesium bromide, isobutylmagnesium chloride, isobutylmagnesium bromide, tert-butylmagnesium chloride or tert-butylmagnesium bromide; the corresponding R group is methyl, ethyl, vinyl, ethynyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
Claims
6. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride
of claim 1, wherein, in step 2), the general formula compound (III) or its solution
is prepared through workup for a reaction in the next step.
7. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride
of claim 1, wherein, in step 3), the reaction temperature is 30-60 °C , and the
hydrogen pressure is 0.5-1 Mpa.
8. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride
of claim 1, wherein the catalyst is any one or more of palladium-carbon,
rhodium-carbon, platinum-carbon and platinum oxide.
9. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride
of claim 7, wherein, in step 3), the catalyst is palladium-carbon.
10. The method for synthesizing cyclopropyl-containing chiral amine hydrochloride
of claim 1, wherein, in step 4), the resolution reagent is (S)-mandelic acid, the
molar ratio of the general formula compound (IV) and the resolution reagent is
1:0.8-1.5, the solvent is isopropanol, and the compound (V) is prepared through
conversion into hydrochloride after resolution.
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| PCT/CN2021/086610 WO2022126942A1 (en) | 2020-12-18 | 2021-04-12 | Synthesis method for cyclopropyl-containing chiral amine hydrochloride |
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| WO2020079145A1 (en) * | 2018-10-18 | 2020-04-23 | Boehringer Ingelheim International Gmbh | Scalable synthesis of optically active 1-cyclopropylalkyl-1-amines |
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