AU2021100766A4 - A Preparation Method of (S)-(+)-2, 2-dimethyl cyclopropanecarboxamide - Google Patents

Abstract

The invention discloses a preparation method of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide, specifically including the following steps. 1) Asymmetric cyclopropanation. Diazoacetate and isobutene are catalyzed by a chiral ligand complex of cuprous salt, and then (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate is obtained by cyclopropylation. 2) Catalytic amidation of cyclopropanecarboxylate. (S)-(+)-2, 2 dimethyl cyclopropanecarboxamide is directly synthesized by one-step ammonolysis of (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate. The chemical purity of refined amide by alcohol is higher than 99.5% and e.e. value is greater than 99.5% as well. The invention relates to a green, environmentally friendly, simple and efficient preparation method of (S) (+)-2, 2-dimethyl cyclopropanecarboxamide.

Description

A Preparation Method of (S)-(+)-2, 2-dimethyl cyclopropanecarboxamide

TECHNICAL FIELD

The invention belongs to the field of chemical engineering, particularly related to dimethyl

cyclopropanecarboxamide, particularly to a preparation method of (S)-(+)-2, 2- dimethyl

cyclopropanecarboxamide.

BACKGROUND

Cilastatin is an inhibitor of renal dehydropeptidase, which can improve the stability of

Imipenem in vivo. Clinical experiments show that a compound preparation of cilastatin

and Imipenem, is especially suitable for the treatment of combined infection of multiple

bacteria and mixed infection of aerobic and anaerobic bacteria. (S)-(+)-2,2- dimethyl

cyclopropanecarboxamide with the molecular formula in Fig. 1 is one of the key

intermediates in the synthesis of cilastatin. The preparation methods of (S)-(+)-2,2

dimethyl cyclopropanecarboxamide mainly include: 1) taking dimethyl malonate as the

starting material, and sequentially carrying out cyclopropanation, saponification,

hydrolysis, heating, decarboxylation and amidation reaction. The total yield of this method

is 22% [Chin. J. Org. Chem, 2008, 28 (2): 308-310], but this method can only synthesize

racemic dimethyl cyclopropanecarboxamide. 2) Isovaleric acid is used as the main starting

material, and then preparing dimethyl cyclopropanecarboxamide by esterification,

cyclopropanation, hydrolysis, esterification, salt formation, fractional crystallization and

aminolysis reaction. Although the reaction conditions of each step are mild, the process is

relatively simple, the enantiomeric excess can reach more than 95.6%. But this method has

a long reaction route with only about 12% total yield. [Tetrahederon: Asymmetry, 1998, 9

(22): 3971-3977] The resolution agents reported in the literature are D-phenylethylamine,

L-camitine oxalate, L-menthol, (S) - methyl mandelate, etc. Although these resolution

agents can resolve dimethyl cyclopropanecarboxylic acid, the yields are between 20% and

%, which are relatively low. In addition, the steps of synthesizing acyl chloride from

acid and then producing amide make the yield of amide low. 3) Synthesis of (S)-(+)-2,2

dimethyl cyclopropanecarboxamide by the biological method. Using R-amidase produced

bacteria to selectively hydrolyze (R)-2, 2-dimethyl cyclopropanecarboxamide in racemic

dimethyl cyclopropanecarboxamide. Lonza company in Switzerland has successfully

adopted this process to produce (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide [Adv.

Synth. Catal., 2003, 345 (4): 425-435.]. Through this method, the e.e. value is over 95%,

but the selective amidase is few, and the production cost is very high. 4) Using chiral metal

complexes as catalysts, dimethyl cyclopropanecarboxylate is synthesized by asymmetric

synthesis method, and the value of e.e. is up to 92% above [J. Am. Chem. Soc., 1991, 113

(2): 726-728]

SUMMARY

In view of the drawbacks in the reported examples, the present invention provides a

preparation method of chiral dimethyl cyclopropanecarboxamide compound, which aims

to solve the technical problems of low yield and high cost of the preparation method in the

prior art.

The invention relates to a preparation method of a chiral dimethyl

cyclopropanecarboxamide compound, which comprises the following steps.

(1) Preparation of (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate. Weighing isobutylene

and diazoacetate, wherein the molar ratio of isobutylene to diazoacetate is 0.8-1.2: 0.8-1.2.

Then weighing chiral catalyst, wherein the additional amount of the chiral catalyst is 0.5

3% of the mass of isobutylene. And then the halogenated hydrocarbon solvent is measured,

and the volume ratio of halogenated hydrocarbon solvent to isobutene is 1-3: 1. Chiral

catalyst is added into a reaction vessel, then halogenated hydrocarbon solvent and

isobutene are added, and diazoacetate is finally added. Under the action of chiral catalyst,

isobutene and diazoacetate are subjected to cyclopropanation reaction in a halogenated

hydrocarbon solvent at -25-25C for 2-3 h. (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate

is obtained by acid washing, alkali washing, and distillation sequentially.

(2) Catalytic amidation of (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate. Specifically,

(S)-(+)-2,2- dimethyl cyclopropanecarboxylate and a catalyst are respectively weighed,

wherein the mass ratio of catalyst to (S)-(+)-2,2-dimethyl cyclopropanecarboxylate is 0.01

0.09:1. Under the action of catalyst, (S)-(+)-2,2-dimethyl cyclopropanecarboxylate

undergoes ammonolysis reaction in an alcohol solution of ammonia at 25-120 °C for24

h. The (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide is obtained by desolvation,

extraction and re-desolvation.

(3) Purification of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide. Crystallize (S)-(+)-2,

2- dimethyl cyclopropanecarboxamide with alcohol or a mixture of alcohol and acid.

Wherein, the alcohol is selected from any one of methanol, ethanol, propanol and n

butanol, and the acid is selected from any one of formic acid, acetic acid, propionic acid,

L-tartaric acid, L-malic acid, L-DTTA and L-mandelic acid. The chemical purity of refined

(S)-(+)-2, 2- dimethyl cyclopropanecarboxamide is higher than 99.5% and e.e. value is

greater than 99.5%.

Further, the carboxyl group in the diazoacetate is selected from C1-C6 alkyl or benzyl.

Specifically, the C1-C6 alkyl group is methyl, ethyl, isopropyl, tert-butyl, or benzyl.

Further, in the step (1), in the asymmetric cyclopropanation reaction, the chiral copper

reagent used is a complex formed by cuprous salt and chiral ligand, and the haloalkane

reagent is monohalogenated or polyhalogenated alkane of C1-C4.

Further, in step (1), the cuprous salt is selected from any one of cuprous chloride, cuprous

bromide, cuprous iodide, cuprous trifluoroacetate or cuprous trifluoromethanesulfonate,

and the chiral ligand is selected from (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2

oxazoline), (R,R)-(+)-2,2'-isopropylidenebis (4-phenyl-2-oxazoline), (R,R)-(+)-2,2'

isopropylidenebis (4-benzyl-2-oxazoline) and (R,R)-(+)-2,2'-isopropylidenebis (4

isopropyl-2-oxazoline).

Further, the haloalkane reagent is monohalogenated or polyhalogenated alkane of C1-C4,

specifically selected from any one of dichloromethane, chloroform, 1,2-dichloroethane,

chloropropane or chlorobutane.

Further, in the step (2), catalytic amidation reaction, the alcohol used is C1-C6 aliphatic

alcohol selected from any one of methyl alcohol, ethanol, propanol, isopropanol and n

butanol, and the catalyst is Lewis acid selected from any one of magnesium chloride,

aluminum chloride, cobalt chloride, calcium chloride, nickel chloride and ferric chloride.

Further, in the alcohol solution of ammonia, the volume ratio of ammonia to alcohol is 1:

1-10, preferably a saturated alcohol solution of ammonia.

Further, in step (3), the alcohol is selected from any one of methanol, ethanol, propanol

and n-butanol, and the acid is selected from any one of formic acid, acetic acid, propionic

acid, L-tartaric acid, L-malic acid, L-DTTA and L-mandelic acid, and its concentration ranges from 0.5 to 3 mol/L. Specifically, in the step (3), when the alcohol and the acid are mixed, the volume ratio of the alcohol to the acid is 1: 0.5-1: 2.

Further, in step (1), the acid is an aqueous solution of any one of sulfuric acid, hydrochloric

acid, acetic acid and phosphoric acid, with concentration ranges from 0.5 to 3 mol/L.

Besides, the alkali is an aqueous solution of any one of sodium carbonate, potassium

carbonate, sodium bicarbonate, and potassium bicarbonate, with a concentration range of

between 0.5 and 3 mol/L.

The synthetic route of the invention is as follows:

+ N 2CH 2C0 2Et cat H cat.H 2 3 'CO 2 Et NH3 'CONH 2

The principle of the invention is as follows. Diazoacetate is prepared by diazotization of

glycine ester hydrochloride. And then diazoacetate and isobutene are catalyzed by chiral

ligand complex of cuprous salt, and then (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate is

obtained by cyclopropylation. (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide is directly

synthesized by one-step ammonolysis of (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate.

The chemical purity of refined amide by alcohol is higher than 99.5% and e.e. value is

greater than 99.5% as well.

The method disclosed by the invention is a green, environment-friendly, simple and

efficient method for synthesizing (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide, with

the e.e. value greater than 99.5 %.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is the HNMR spectrum of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide

obtained from Embodiments 1-9.

DESCRIPTION OF THE INVENTION

Specific embodiments and figures will further illustrate the present invention, but it is not

limited to this.

Embodiment 1

+ N2 CH 2 C0 2 Et cat.

The method for preparing the (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate specifically

comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2-oxazoline) (1.74 g, 5.94 mmol),

cuprous trifluoromethanesulfonate (1.14 g, 5.4 mmol) and dichloromethane (250 ml) into

a 1000 ml three-neck flask with a thermometer and dropping funnel, and stir for 2 h at room

temperature (25-30°C). The reaction system was then cooled to -5 - 0 °C and isobutylene

was added to saturate, and then ethyl diazoacetate (114 g, 1 mol) was added slowly. The

temperature of the reaction system was controlled to 0 °C, and then the system was slowly

heated to room temperature (25 °C) and stirred for 1 h. After TLC detected the EDA

consumption, the system was depressurized and concentrated (T < 30 °C, - 0.09 MPa) to

obtain the crude product. Finally, 90 g of main distillate fraction was obtained by vacuum

distillation of crude product, with GC > 98 %, e.e. value > 95%.

Embodiment 2

+ N 2CH 2 CO2 i-Pr cat. H 'CO2i-Pr

The method for preparing the (S)-(+)-2, 2-isopropyl dimethyl cyclopropanecarboxylate

specifically comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2-oxazoline) (1.74 g, 5.94 mmol),

cuprous trifluoromethanesulfonate (1.14 g, 5.4 mmol) and dichloromethane (250 ml) into

a 1000 ml three-neck flask with thermometer and dropping funnel, and stir for 2 h at room

temperature (25-30 °C). The reaction system was then cooled to -5 - 0 °C and isobutylene

was added to saturate, and then isopropyl diazoacetate (129 g, 1 mol) was added slowly.

The temperature of the reaction system was controlled to 0 °C, and then the system was

slowly heated to room temperature (25 °C) and stirred for 1 h. After the TLC detected the

EDA consumption, the system was depressurized and concentrated (T < 30 °C, - 0.09 MPa)

to obtain the crude product. Finally, 100 g of main distillate fraction was obtained by

vacuum distillation of crude product, with GC > 98 %, e.e. value > 95%.

Embodiment 3

cat. H + N 2CH 2 CO 2Me 'CO Me 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxylate specifically

comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2-oxazoline) (1.74 g, 5.94 mmol),

cuprous trifluoromethanesulfonate (1.14 g, 5.4 mmol) and dichloromethane (250 ml) into

a 1000 ml three-neck flask with thermometer and dropping funnel, and stir for 2 h at room

temperature (25-30 °C). The reaction system was then cooled to -5 - 0 °C and isobutylene

was added to saturate, and then methyl diazoacetate (101 g, 1 mol) was added slowly. The

temperature of the reaction system was controlled to 0 °C, and then the system was slowly

heated to room temperature (25 °C) and stirred for 1 h. After the TLC detected the EDA

consumption, the system was depressurized and concentrated (T < 30 °C, - 0.09 MPa) to obtain the crude product. Finally, 88 g of main distillate fraction was obtained by vacuum distillation of crude product, with GC > 98 %, e.e. value > 95%.

Embodiment 4

+ N 2 CH 2 CO2 Et cat >EH

The method for preparing the (S)-(+)-2, 2- ethyl dimethyl cyclopropanecarboxylate

specifically comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-phenyl-2-oxazoline) (1.98 g, 5.94 mmol), cuprous

trifluoromethanesulfonate (1.14 g, 5.4 mmol) and dichloromethane (250 ml) into a 1000

ml three-neck flask with thermometer and dropping funnel, and stir for 2 h at room

temperature (25-30 °C). The reaction system was then cooled to -5 - 0 °C and isobutylene

was added to saturate, and then ethyl diazoacetate (114 g, 1 mol) was added slowly. The

temperature of the reaction system was controlled to 0 °C, and then the system was slowly

heated to room temperature (25 °C) and stirred for 1 h. After the TLC detected the EDA

consumption, the system was depressurized and concentrated (T < 30 °C, - 0.09 MPa) to

obtain the crude product. Finally, 92 g of main distillate fraction was obtained by vacuum

distillation of crude product, with GC > 98 %, e.e. value > 95%.

Embodiment 5

+ N 2 CH 2 CO2 Et cat 0

The method for preparing the (S)-(+)-2, 2- ethyl dimethyl cyclopropanecarboxylate

specifically comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-benzyl-2-oxazoline) (2.15 g, 5.94 mmol), cuprous

trifluoromethanesulfonate (1.14 g, 5.4 mmol) and dichloromethane (250 ml) into a 1000

ml three-neck flask with a thermometer and dropping funnel, and stir for 2 h at room

temperature (25-30 °C). The reaction system was then cooled to -5 - 0 °C and isobutylene

was added to saturate, and then ethyl diazoacetate (114 g, 1 mol) was added slowly. The

temperature of the reaction system was controlled to 0 °C, and then the system was slowly

heated to room temperature (25 °C) and stirred for 1 h. After the TLC detected the EDA

consumption, the system was depressurized and concentrated (T < 30 °C, - 0.09 MPa) to

obtain the crude product. Finally, 89 g of main distillate fraction was obtained by vacuum

distillation of crude product, with GC > 98 %, e.e. value > 95%.

Embodiment 6

+ N 2 CH 2 CO2 Et cat 02Et

The method for preparing the (S)-(+)-2, 2- ethyl dimethyl cyclopropanecarboxylate

specifically comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2-oxazoline) (1.74 g, 5.94 mmol),

cuprous chloride (0.54 g, 5.4 mmol) and dichloromethane (250 ml) into a 1000 ml three

neck flask with thermometer and dropping funnel, and stir for 2 h at room temperature (25

°C). The reaction system was then cooled to -5 - 0 °C and isobutylene was added to

saturate, and then ethyl diazoacetate (114 g, 1 mol) was added slowly. The temperature of

the reaction system was controlled to 0 °C, and then the system was slowly heated to room

temperature (25 °C) and stirred for 1 h. After the TLC detected the EDA consumption, the

system was depressurized and concentrated (T < 30 °C, - 0.09 MPa) to obtain the crude product. Finally, 93g of main distillate fraction was obtained by vacuum distillation of crude product, with GC > 98 %, e.e. value > 93%.

Embodiment 7

+ N 2 CH 2 CO2 Et cat >EH

The method for preparing the (S)-(+)-2, 2- ethyl dimethyl cyclopropanecarboxylate

specifically comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2-oxazoline) (1.74 g, 5.94 mmol),

cuprous iodide (1.03 g, 5.4 mmol) and dichloromethane (250 ml) into a 1000 ml three-neck

flask with thermometer and dropping funnel, and stir for 2 h at room temperature (25-30

°C). The reaction system was then cooled to -5 - 0 °C and isobutylene was added to

saturate, and then ethyl diazoacetate (114 g, 1 mol) was added slowly. The temperature of

the reaction system was controlled to 0 °C, and then the system was slowly heated to room

temperature (25 °C) and stirred for 1 h. After the TLC detected the EDA consumption, the

system was depressurized and concentrated (T < 30 °C, - 0.09 MPa) to obtain the crude

product. Finally, 97 g of main distillate fraction was obtained by vacuum distillation of

crude product, with GC > 98 %, e.e. value > 94%.

Embodiment 8

+ N 2 CH 2 CO2 Et cat 0

The method for preparing the (S)-(+)-2, 2- ethyl dimethyl cyclopropanecarboxylate

specifically comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2-oxazoline) (1.74 g, 5.94 mmol),

cuprous iodide (1.03 g, 5.4 mmol) and dichloromethane (250 ml) into a 1000 ml three-neck

flask with thermometer and dropping funnel, and stir for 2 h at room temperature (25-30

°C). The reaction system was then cooled to -25 °C and isobutylene was added to saturate,

and then ethyl diazoacetate (114 g, 1 mol) was added slowly. The temperature of the

reaction system was controlled to -25 °C, and then the system was stirred for 3 h. After the

TLC detected the EDA consumption, the system was depressurized and concentrated (T <

°C, - 0.09 MPa) to obtain the crude product. Finally, 87 g of main distillate fraction was

obtained by vacuum distillation of crude product, with GC > 98 %, e.e. value > 96%.

Embodiment 9

+ N2 CH 2 CO2 Et cat >EH

The method for preparing the (S)-(+)-2, 2- ethyl dimethyl cyclopropanecarboxylate

specifically comprises the following steps.

Add (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2-oxazoline) (1.74 g, 5.94 mmol),

cuprous iodide (1.03 g, 5.4 mmol) and dichloromethane (250 ml) into a 1000 ml three-neck

flask with thermometer and dropping funnel, and stir for 2 h at room temperature (25-30

°C). The reaction system was then cooled to -20 - 25 °C and isobutylene was added to

saturate, and then ethyl diazoacetate (114 g, 1 mol) was added slowly. The temperature

of the reaction system was controlled to 20-25 °C, and then the system was stirred for 1 h.

After the TLC detected the EDA consumption, the system was depressurized and

concentrated (T < 30 °C, - 0.09 MPa) to obtain the crude product. Finally, 102 g of main distillate fraction was obtained by vacuum distillation of crude product, with GC > 98 %, e.e. value > 94%.

Embodiment 10

H NH 3 , cat. H 'CO 2 Me ''CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2- dimethyl cyclopropanecarboxylate (12.8 g, 0.1 mol), anhydrous calcium

chloride (13.3 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia saturated solution

prepared at 0 -5 °C) into a 250 ml autoclave. When the temperature raised to 100 -110 °C

, stirring 18-20 h for reaction. After reducing to room temperature, the reaction solution

was concentrated under reduced pressure, and then water (30 ml) was added to raise the

temperature and reflux. After dissolving and clarifying, the reaction solution was reduced

to room temperature and stirred in ice water bath for 1 h. The white solid precipitated and

filtered out. The aqueous phase was extracted with ethyl acetate (50 ml * 2) and the organic

phase was concentrated to obtain a total of 9 g solid with e.e. > 95%.

Embodiment 11

H NH3, cat. H 'CO 2 Me 'CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2- dimethyl cyclopropanecarboxylate (14.2 g, 0.1 mol), anhydrous calcium

chloride (13.3 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia saturated solution

prepared at 0 -5 °C) into a 250 ml autoclave. When the temperature raised to 100 -110 °C stirring 18-20 h for reaction. After reducing to room temperature, the reaction solution was concentrated under reduced pressure, and then water (30 ml) was added to raise the temperature and reflux. After dissolving and clarifying, the reaction solution was reduced to room temperature and stirred in ice water bath for 1 h. The white solid precipitated and filtered out. The aqueous phase was extracted with ethyl acetate (50 ml * 2) and the organic phase was concentrated to obtain a total of 10 g solid with e.e. > 95%.

Embodiment 12

H NH 3 , cat. H 'CO 2 Me ''CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2- dimethyl cyclopropanecarboxylate (15.6 g, 0.1 mol), anhydrous calcium

chloride (13.3 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia saturated solution

prepared at 0 -5 °C) into a 250 ml autoclave. When the temperature raised to 100 -110

°C, stirring 18-20 h for reaction. After reducing to room temperature, the reaction solution

was concentrated under reduced pressure, and then water (30 ml) was added to raise the

temperature and reflux. After dissolving and clarifying, the reaction solution was reduced

to room temperature and stirred in ice water bath for 1 h. The white solid precipitated and

filtered out. The aqueous phase was extracted with ethyl acetate (50 ml * 2) and the organic

phase was concentrated to obtain a total of 10 g solid with e.e. > 95%.

Embodiment 13

H NH 3 , cat. H ''CO 2 Me ''CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2- dimethyl cyclopropanecarboxylate (12.8 g, 0.1 mol), anhydrous calcium

chloride (15.6 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia saturated solution

prepared at 0 -5 °C) into a 250 ml autoclave. When the temperature raised to 100 -110

°C, stirring 18-20 h for reaction. After reducing to room temperature, the reaction solution

was concentrated under reduced pressure, and then water (30 ml) was added to raise the

temperature and reflux. After dissolving and clarifying, the reaction solution was reduced

to room temperature and stirred in ice water bath for 1 h. The white solid precipitated and

filtered out. The aqueous phase was extracted with ethyl acetate (50 ml * 2) and the organic

phase was concentrated to obtain a total of 8 g solid with e.e. > 95%.

Embodiment 14

H NH 3 , cat. H 'CO 2 Me 'CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2- Dimethyl cyclopropanecarboxylate (12.8 g, 0.1 mol), anhydrous calcium

chloride (15.6 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia saturated solution

prepared at 0 -5 °C) into a 250 ml autoclave. When the temperature raised to 100 -110 °C

, stirring 18-20 h for reaction. After reducing to room temperature, the reaction solution

was concentrated under reduced pressure, and then water (30 ml) was added to raise the

temperature and reflux. After dissolving and clarifying, the reaction solution was reduced

to room temperature and stirred in ice water bath for 1 h. The white solid precipitated and filtered out. The aqueous phase was extracted with ethyl acetate (50 ml * 2) and the organic phase was concentrated to obtain a total of 8 g solid with e.e. > 95%.

Embodiment 15

H NH 3 , cat. H 'CO 2 Me ''CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2- dimethyl cyclopropanecarboxylate (12.8 g, 0.1 mol), anhydrous

magnesium chloride (11.4 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia

saturated solution prepared at 0 -5 °C) into a 250 ml autoclave. When the temperature

raised to 100 -110 °C, stirring 18-20 h for reaction. After reducing to room temperature,

the reaction solution was concentrated under reduced pressure, and then water (30 ml) was

added to raise the temperature and reflux. After dissolving and clarifying, the reaction

solution was reduced to room temperature and stirred in ice water bath for 1 h. The white

solid precipitated and filtered out. The aqueous phase was extracted with ethyl acetate (50

ml * 2) and the organic phase was concentrated to obtain a total of 9 g solid with e.e. >

%.

Embodiment 16

H NH 3 , cat. H ''CO 2 Me ''CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2- dimethyl cyclopropanecarboxylate (12.8 g, 0.1 mol), anhydrous cobalt

chloride (15.5 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia saturated solution prepared at 0 -5 °C) into a 250 ml autoclave. When the temperature raised to 100 -110 °C

, stirring 18-20 h for reaction. After reducing to room temperature, the reaction solution

was concentrated under reduced pressure, and then water (30 ml) was added to raise the

temperature and reflux. After dissolving and clarifying, the reaction solution was reduced

to room temperature and stirred in ice water bath for 1 h. The white solid precipitated and

filtered out. The aqueous phase was extracted with ethyl acetate (50 ml * 2) and the organic

phase was concentrated to obtain a total of 9 g solid with e.e. > 95%.

Embodiment 17

AA H NH3, cat. H 'CO 2 Me 'CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2- dimethyl cyclopropanecarboxylate (12.8 g, 0.1 mol), anhydrous

magnesium chloride (11.4 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia

saturated solution prepared at 0 -5 °C) into a 250 ml autoclave. Stirring 18-20 h for reaction

at room temperature. After reducing to room temperature, the reaction solution was

concentrated under reduced pressure, and then water (30 ml) was added to raise the

temperature and reflux. After dissolving and clarifying, the reaction solution was reduced

to room temperature and stirred in ice water bath for 1 h. The white solid precipitated and

filtered out. The aqueous phase was extracted with ethyl acetate (50 ml * 2) and the organic

phase was concentrated to obtain a total of 6 g solid with e.e. > 95%.

Embodiment 18

H NH 3 , cat. H 'CO2 Me ''CONH 2

The method for preparing the (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide specifically

comprises the following steps.

Add (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate (12.8 g, 0.1 mol), anhydrous

magnesium chloride (11.4 g, 0.12 mmol) and methanol ammonia (140 ml, ammonia

saturated solution prepared at 0-5 °C) into a 250 ml autoclave. When the temperature raised

to 50-60 °C, stirring 18-20 h for reaction. After reducing to room temperature, the reaction

solution was concentrated under reduced pressure, and then water (30 ml) was added to

raise the temperature and reflux. After dissolving and clarifying, the reaction solution was

reduced to room temperature and stirred in ice water bath for 1 h. The white solid

precipitated and filtered out. The aqueous phase was extracted with ethyl acetate (50 ml*

2) and the organic phase was concentrated to obtain a total of 8 g solid with e.e. > 95%.

Embodiment 19

The method for purifying the above-mentioned (S)-(+)-2, 2- dimethyl

cyclopropanecarboxamide specifically comprises the following steps.

Ina 100 ml three-neck flask with a thermometer and a dropping funnel, 5 g crudeproduct

of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide and 15 ml of methanol were added,

heated and refluxed for 1 h, cooled gradually (within 3 h) to room temperature, stirred for

1 h, and filtered to obtain 3.5 g of white solid with a yield of 75% and an e.e. value of

higher than 99.5%.

Avance 500 MHz nuclear magnetic spectrometer and Dionex MSOPlus mass spectrometer

were used to determine the white solid. The results of NMR and MS data are as follows:

1H NMR (500 MHz, CDCl3) 6 7.42 (br, 1H), 6.68 (br, 1H), 1.33 (dd, J= 7.7, 5.4 Hz, 1H),

1.09 (s, 6H), 0.88 (t, J = 4.6 Hz, 1H), 0.70 (dd, J = 7.7, 4.3 Hz, 1H). ESI-MS(m/z): 114.3

(M+1)+.

Furthermore, the NMR spectrum is shown in Fig. 1;

From the above NMR data, MS data and NMR spectra, it can be concluded that the

structural formula of the white solid obtained above is as follows:

,' H

s)''CONH2, that is, (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide

Embodiment 20

The method for purifying the above-mentioned (S)-(+)-2, 2- dimethyl

cyclopropanecarboxamide specifically comprises the following steps.

Ina 100 ml three-neck flask with a thermometer and a dropping funnel, 5 g crudeproduct

of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide, 10 ml of methanol and 1 ml acetic

acid were added, heated and refluxed for 1 h, cooled gradually (within 3 h) to room

temperature, stirred for 1 h, and filtered to obtain 4.5 g of white solid with a yield of 90%

and an e.e. value of more than 99.5%.

From the NMR data, MS data and NMR spectra, it can be concluded that the structural

formula of the white solid obtained above is as follows:

>'YCnVH (s)'CONH2, namely, (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide

Embodiment 21

The method for purifying the above-mentioned (S)-(+)-2, 2- dimethyl

cyclopropanecarboxamide specifically comprises the following steps.

Ina 100 ml three-neck flask with a thermometer and a dropping funnel, 5 g crudeproduct

of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide, 10 ml ethanol and 1 ml acetic acid

were added, heated and refluxed for 1 h, cooled gradually (within 3 h) to room temperature,

stirred for 1 h, and filtered to obtain 4.6 g of white solid with a yield of 95% and an e.e.

value of more than 99.5%.

From the above NMR data, MS data and NMR spectra, it can be concluded that the

structural formula of the white solid obtained above is as follows:

,' H

(s)''CONH2, namely, (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide

Embodiment 22

The method for purifying the above-mentioned (S)-(+)-2, 2- dimethyl

cyclopropanecarboxamide specifically comprises the following steps.

Ina 100 ml three-neck flask with a thermometer and a dropping funnel, 5 g crudeproduct

of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide and 10 ml isopropanol and 1 ml acetic

acid were added, heated and refluxed for 1 h, cooled gradually (within 3 h) to room

temperature, stirred for 1 h, and filtered to obtain 4.6 g of white solid with a yield of 92%

and an e.e. value of more than 99.5%.

From the above NMR data, MS data and NMR spectra, it can be concluded that the

structural formula of the white solid obtained above is as follows:

>'YCnVH s)''CONH2, that is, (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide

The above embodiments are only used to illustrate the present invention and are not used

to limit the scope of the present invention. In addition, after reading the present invention,

those skilled in the field can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (2)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A preparation method of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide, characterized

by comprising the following steps.

(1) Preparation of (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate. Weighing isobutylene

and diazoacetate, wherein the carboxyl group in the diazoacetate is selected from C1-C6

alkyl or benzyl, and the molar ratio of isobutylene to diazoacetate is 0.8-1.2: 0.8-1.

2. Then

weighing chiral catalyst, which is a complex formed by cuprous salt and chiral ligand.

Further, the cuprous salt is selected from any one of cuprous chloride, cuprous bromide,

cuprous iodide, cuprous trifluoroacetate or cuprous trifluoromethanesulfonate, and the

chiral ligand is selected from (R,R)-(+)-2,2'-isopropylidenebis (4-tert-butyl-2-oxazoline),

(R,R)-(+)-2,2'-isopropylidenebis (4-phenyl-2-oxazoline), (R,R)-(+)-2,2'-isopropylidenebis

(4-benzyl-2-oxazoline) and (R,R)-(+)-2,2'-isopropylidenebis (4-isopropyl-2-oxazoline).

Besides, the addition amount of the chiral catalyst is 0.5-3% of the mass of isobutylene.

And then the halogenated hydrocarbon solvent is measured, which is anyone selected from

dichloromethane, chloroform, 1,2-dichloroethane, chloropropane or chlorobutane. The

volume ratio of halogenated hydrocarbon solvent to isobutene is 1-3: 1. Chiral catalyst is

added into a reaction vessel, then halogenated hydrocarbon solvent and isobutene are

added, and diazoacetate is finally added. Under the action of chiral catalyst, isobutene and

diazoacetate are subjected to cyclopropanation reaction in halogenated hydrocarbon

solvent at -25-25C for 2-3 h. (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate is obtained

by acid washing, alkali washing and distillation sequentially. Wherein, the acid is an

aqueous solution of any one of sulfuric acid, hydrochloric acid, acetic acid and phosphoric acid, and the alkali is an aqueous solution of any one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

(2) Catalytic amidation of (S)-(+)-2, 2-dimethyl cyclopropanecarboxylate. Specifically,

(S)-(+)-2,2- dimethyl cyclopropanecarboxylate and a catalyst are respectively weighed,

wherein the catalyst is Lewis acid selected from any one of magnesium chloride, aluminum

chloride, cobalt chloride, calcium chloride, nickel chloride and ferric chloride. The mass

ratio of catalyst to (S)-(+)-2,2- dimethyl cyclopropanecarboxylate is 0.01-0.09:1. Under

the action of catalyst, (S)-(+)-2,2- dimethyl cyclopropanecarboxylate undergoes

ammonolysis reaction in an alcohol solution of ammonia, wherein the alcohol used is Cl

C6 aliphatic alcohol, and the volume ratio of ammonia to alcohol in the alcohol solution of

ammonia is 1: 1-10. The reaction temperature is 25-120 °C and the reaction time is 24

h. The (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide is obtained by desolvation,

extraction and re-desolvation.

(3) Purification of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide. Crystallize (S)-(+)-2,

2- dimethyl cyclopropanecarboxamide with alcohol or mixture of alcohol and acid.

Wherein, the alcohol is selected from any one of methanol, ethanol, propanol and n

butanol, and the acid is selected from any one of formic acid, acetic acid, propionic acid,

L-tartaric acid, L-malic acid, L-DTTA and L-mandelic acid. The chemical purity of refined

(S)-(+)-2, 2- dimethyl cyclopropanecarboxamide is higher than 99.5% and e.e. value is

greater than 99.5% as well.

- 08 Feb 2021

-1/1- 2021100766

Figure 1

The HNMR spectrum of (S)-(+)-2, 2- dimethyl cyclopropanecarboxamide obtained from

Embodiments 1-9.