CN112552184B - Synthetic method of cyclopropyl-containing chiral amine hydrochloride - Google Patents
Synthetic method of cyclopropyl-containing chiral amine hydrochloride Download PDFInfo
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- 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 invention discloses a synthetic method of a pharmaceutical intermediate cyclopropyl-containing chiral amine hydrochloride, belonging to the field of synthetic preparation of pharmaceutical intermediates. The invention takes compound (I) cyclopropanecarboxaldehyde as an initial raw material, and obtains a target product chiral amine hydrochloride through condensation, alkylation, debenzylation, chiral resolution and salt forming reaction. The synthesis method of the medicine intermediate cyclopropyl chiral amine hydrochloride has the characteristics of low cost and simplicity in operation.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates and organic chemical intermediates, and relates to a synthesis method of chiral amine hydrochloride containing cyclopropyl.
Background
Cyclopropyl chiral amine is an important medical intermediate, and has wide application, for example, the cyclopropyl chiral amine can be used for synthesizing corticotropin releasing factor-1 (CRF1) receptor antagonists (J.Med.chem.2009,52,4173) in literature, can be used for synthesizing quinazoline medicaments for treating cancers (ACS Med.chem.Lett.2018,9,9,941-946), can be used for synthesizing Cathepsin S inhibitors for treating autoimmunity and related diseases in patents (WO2011109470), and can be used for synthesizing Ras regulating active agents for treating cancers in patents (WO 2018212774). In a word, the cyclopropyl chiral amine has wide application in the field of medical synthesis at present, and the synthesis process has higher development value.
The synthesis of cyclopropyl chiral amine compound has difficulty in forming chiral amine structure, and there are two general synthetic strategies, which are reviewed in the following:
the first method, (j.med.chem.2009,52,4173) and other patents report that N-methoxy-N-methyl-2-methoxyacetamide is used as a raw material, and a target product is generated through cyclopropanation, reductive amination, Cbz protection, chiral resolution and deprotection reactions, wherein the route needs 5 steps, a long reaction route and expensive raw materials, the chiral resolution needs to be carried out by using an HPLC chiral column, and the method cannot be scaled up for industrialization, and the reductive amination also uses a large amount of sodium triacetyl borohydride, has a large explosion risk, and is not suitable for industrial production.
Another method, the document ACS Med. chem. Lett.2018,9, 941-946 reports that cyclopropanecarboxaldehyde is used as a raw material, firstly condensed with chiral tert-butyl sulfinamide, then alkylated with a Grignard reagent, and finally removed with tert-butyl sulfinyl to obtain a product. The chiral tertiary butyl sulfinamide used in the route is expensive, generates an odor gas, and is not suitable for industrial production due to the fact that multi-step reaction involves column purification operation.
The existing synthetic routes have the defects of long steps, need to use expensive reagents, relate to flammable and explosive dangerous reagents or production processes, need special production equipment, cause serious environmental pollution and the like, and are not beneficial to large-scale industrial production. Therefore, the method for preparing cyclopropyl chiral amine has the advantages of simple reaction, low cost and easy industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the synthesis method of chiral amine hydrochloride containing cyclopropyl is developed, has the advantages of easily obtained raw materials, higher yield, better quality and simple and convenient operation, and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
the specific synthetic process comprises the following steps:
the method comprises the following steps of (1) condensing cyclopropanecarboxaldehyde (compound (I)) serving as a starting material with (R) -1-phenylethylamine to obtain a compound (II), alkylating the compound (II) with a corresponding Grignard reagent to obtain a compound (III) in a general formula, hydrogenating and debenzylating the compound to obtain a compound (IV) in the general formula, and splitting the compound to form a salt to obtain a compound (V) in the general formula.
A synthetic method of chiral amine hydrochloride containing cyclopropyl comprises the following synthetic steps:
step 1), enabling cyclopropane formaldehyde of a compound (I) to serve as a starting material to be condensed with (R) -1-phenylethylamine to prepare a compound (II), enabling the compound (I) and the (R) -1-phenylethylamine to react in a solvent at the temperature of 50-110 ℃, and performing post-treatment to obtain the compound (II) or a solution thereof, wherein the solvent is any one or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane and dichloromethane, and the molar ratio of the cyclopropane formaldehyde to the (R) -1-phenylethylamine is 1: 1-3;
and 2) reacting the compound (II) solution with the Grignard reagent solution at-50-100 ℃, and performing post-treatment to prepare a compound (III) or a solution thereof with the general formula, wherein the molar ratio of the compound (II) to the Grignard reagent is 1: 1-10;
step 3) reacting the solution of the general formula compound (III) at 0-100 ℃ in a hydrogen atmosphere of 0-10 MPa under the catalysis of a catalyst, and performing post-treatment to prepare a general formula compound (IV) or a solution thereof;
and 4) adding a resolving agent and a solvent into the compound (IV) with the general formula or a solution thereof, resolving, and then carrying out post-treatment to convert the compound (IV) into a hydrochloride to prepare the compound (V) with the general formula, wherein the resolving agent is any one or more of (S) -mandelic acid, (S) -acetyl mandelic acid, L-dibenzoyl tartaric 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, and the molar weight ratio of the compound (IV) to the resolving agent is 0: 0.5 to 10;
as a further preferable embodiment, in the step 1), the compound (II) is prepared by reacting cyclopropanecarbaldehyde and (R) -1-phenylethylamine at a molar ratio of 1: 1-1.5, a solvent is toluene and a reaction temperature of 80-110 ℃.
As a further preferred example, in step 1), the compound (II) or the solution is prepared by work-up and subjected to the next reaction.
As a further preferable embodiment, in the step 2), the reaction temperature is-20 to 60 ℃, and the molar ratio of the compound (II) to the grignard reagent is 1:1 to 1.5.
As further preferred examples, the Grignard reagent is methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, vinyl magnesium chloride, vinyl magnesium bromide, ethynyl magnesium chloride, ethynyl magnesium bromide, n-propyl magnesium chloride, n-propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, the corresponding R group is methyl, ethyl, vinyl, ethynyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
as a further preferred example, in step 2), the work-up produces the compound of formula (III) or a solution, which is subjected to the next reaction.
In a further preferred embodiment, in the step 3), the reaction temperature is 30 to 60 ℃ and the hydrogen pressure is 0.5 to 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 on carbon.
As a further preferred example, in step 4), the resolving agent is (S) -mandelic acid, and the molar weight ratio of the compound of formula (IV) to the resolving agent is 0: 0.8-1.5, taking isopropanol as a solvent, and converting into hydrochloride after resolution to obtain the compound (V).
The synthesis method of chiral amine hydrochloride containing cyclopropyl provided by the invention has the following advantages:
the route of the invention is relatively simple, the used raw materials are commercial materials, and the raw materials are relatively cheap, have no complex special operation, and are suitable for industrial production; provides a new synthesis scheme for the synthesis and preparation of chiral amine hydrochloride containing cyclopropyl.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described with reference to the following embodiments:
example 1:
under nitrogen atmosphere, 70.1g of cyclopropane formaldehyde (1.0mol, 1.0eq) and 127.3g of (R) -1-phenylethylamine (1.05mol, 1.05eq) are added into a reaction bottle, dissolved in 700g of toluene, heated to 80-90 ℃, reacted for 12 hours, cooled to 10-20 ℃, added with 100g of 0.1M hydrochloric acid for washing for 1 time, added with 100g of anhydrous magnesium sulfate in the organic phase for drying and filtered, and the prepared compound (II) solution is directly subjected to the next reaction.
And (3) cooling the toluene solution of the compound (II) to-20 ℃, dropwise adding 620mL of tetrahydrofuran solution (1.1mol, 1.1eq) of ethyl magnesium chloride, stirring for 30min after dropwise adding, adding aqueous solution of ammonium chloride for quenching, layering, washing an organic phase once with water to prepare a solution of the compound (III-1), and directly putting the solution into the next reaction.
Putting the solution of the compound (III-1) into an autoclave, adding 5g of 5% Pd/C, replacing with hydrogen, adjusting the pressure to 0.5MPa, reacting for 4h, discharging, filtering to obtain a solution of the compound (IV-1), and putting the solution into the next reaction.
Adding 152.2g of (S) -mandelic acid (1.0mol, 1.0eq) and 200mL of isopropanol into the solution of the compound (IV-1), heating to 70 ℃, stirring for 2h, cooling to 10-20 ℃, filtering, adding 200mL of isopropanol into a filter cake, and pulping for 3h at 20-30 ℃. After the pulping is finished, filtering to obtain a filter cake, adding 500mL of methyl tert-butyl ether and 300mL of 5M sodium hydroxide solution, stirring for 30min, demixing, and taking an organic phase. 350mL of 1, 4-dioxane solution of 4M hydrogen chloride is added into the organic phase, the mixture is stirred for 1 hour, filtered, and the filter cake is dried to obtain 115.7g of white solid, namely the compound (V-1), wherein the yield is 85.3%, the purity is 99.5%, and the ee value is 99%. Compound nuclear magnetic data are as follows:1H NMR(400MHz,D2O):δ2.07(m,1H),δ1.44(m,2H),δ0.68(t,3H),δ0.67(m,1H),δ0.33(m,2H),δ0.03(m,2H)；13C NMR(400MHz,D2O):δ56.6，δ24.0，δ10.6，δ6.9，δ1.5。
example 2:
under nitrogen atmosphere, 70.1g of cyclopropane formaldehyde (1.0mol, 1.0eq) and 145.5g of (R) -1-phenylethylamine (1.2mol, 1.2eq) are added into a reaction bottle, dissolved in 1000g of toluene, heated to 80-90 ℃, reacted for 10 hours, cooled to 10-20 ℃, added with 200g of 0.1M hydrochloric acid for washing for 1 time, added with 100g of anhydrous magnesium sulfate in the organic phase for drying and filtering, and the prepared compound (II) solution is directly subjected to the next reaction.
And (3) cooling the toluene solution of the compound (II) to-20 ℃, dropwise adding 620mL of tetrahydrofuran solution (1.1mol, 1.1eq) of vinyl magnesium bromide, stirring for 30min after dropwise adding, adding aqueous solution of ammonium chloride for quenching, layering, washing an organic phase once with water to prepare a solution of the compound (III-2), and directly putting the solution into the next reaction.
Putting the solution of the compound (III-2) into an autoclave, adding 3g of 5% Pd/C, replacing with hydrogen, adjusting the pressure to 1.0MPa, reacting for 4h, discharging, filtering, and putting the filtrate which is the solution of the compound (IV-2) into the next reaction.
Adding 137.0g of (S) -mandelic acid (0.95mol, 0.95eq) and 200mL of isopropanol into the solution of the compound (IV-2), heating to 70 ℃, stirring for 2h, cooling to 10-20 ℃, filtering, adding 200mL of isopropanol into a filter cake, and pulping for 3h at 20-30 ℃. After the pulping is finished, filtering to obtain a filter cake, adding 500mL of methyl tert-butyl ether and 300mL of 5M sodium hydroxide solution, stirring for 30min, demixing, and taking an organic phase. 350mL of 1, 4-dioxane solution of 4M hydrogen chloride is added into the organic phase, the mixture is stirred for 1 hour, filtered, and the filter cake is dried to obtain 116.8g of white solid, namely the compound (V-2), wherein the yield is 87.4%, the purity is 99.8%, and the ee value is 99.1%. Compound nuclear magnetic data are as follows:1H NMR(400MHz,D2O):δ5.81(m,1H),δ5.28(m,2H),δ3.03(m,1H),δ0.95(m,1H),δ0.43(m,4H)；13C NMR(400MHz,D2O):δ132.5，δ119.4，δ58.3，δ12.8，δ3.3，δ2.6。
example 3:
under nitrogen atmosphere, 70.1g of cyclopropane formaldehyde (1.0mol, 1.0eq) and 133.4g of (R) -1-phenylethylamine (1.1mol, 1.1eq) are added into a reaction bottle, dissolved in 1000g of toluene, heated to 100-105 ℃, reacted for 18 hours, cooled to 10-20 ℃, added with 200g of 0.1M hydrochloric acid and washed for 1 time, added with 100g of anhydrous magnesium sulfate in the organic phase, dried and filtered to prepare a compound (II) solution, and the compound (II) solution is directly subjected to the next reaction.
Cooling the toluene solution of the compound (II) to 20 ℃, dropwise adding 620mL tetrahydrofuran solution (1.1mol, 1.1eq) of isopropyl magnesium chloride, stirring for 30min after dropwise adding, adding aqueous solution of ammonium chloride for quenching, layering, washing the organic phase once with water to prepare a compound (III-3) solution, and directly putting the compound (III-3) solution into the next reaction.
Putting the solution of the compound (III-3) into an autoclave, adding 10g of 5% Pd/C, replacing with hydrogen, adjusting the pressure to 1.0MPa, reacting for 2h, discharging, filtering, and putting the filtrate which is the solution of the compound (IV-3) into the next reaction.
Adding 155.3g of (S) -acetyl mandelic acid (0.8mol, 0.8eq) and 300mL of isopropanol into the solution of the compound (IV-3), heating to 70 ℃, stirring for 2h, cooling to 10-20 ℃, filtering, adding 300mL of isopropanol into the filter cake, and pulping for 3h at 20-30 ℃. After the pulping is finished, filtering to obtain a filter cake, adding 500mL of methyl tert-butyl ether and 300mL of 5M sodium hydroxide solution, stirring for 30min, demixing, and taking an organic phase. 350mL of 1, 4-dioxane solution of 4M hydrogen chloride is added into the organic phase, the mixture is stirred for 1 hour, filtered, and the filter cake is dried to obtain 125.3g of white solid, namely the compound (V-3), wherein the yield is 83.7%, the purity is 99.6%, and the ee value is 99.0%. Compound nuclear magnetic data are as follows:1HNMR(400MHz,D2O):δ2.0(m,1H),δ1.74(m,1H),δ0.74(d,6H),δ0.67(m,1H),δ0.23(m,4H)；13C NMR(400MHz,D2O):δ61.2，δ29.5，δ15.7，δ9.0，δ3.0。
example 4:
under nitrogen atmosphere, 70.1g of cyclopropane formaldehyde (1.0mol, 1.0eq) and 133.4g of (R) -1-phenylethylamine (1.1mol, 1.1eq) are added into a reaction bottle, dissolved in 1000g of toluene, heated to 100-105 ℃, reacted for 18 hours, cooled to 10-20 ℃, added with 200g of 0.1M hydrochloric acid and washed for 1 time, added with 100g of anhydrous magnesium sulfate in the organic phase, dried and filtered to prepare a compound (II) solution, and the compound (II) solution is directly subjected to the next reaction.
And (3) cooling the toluene solution of the compound (II) to 40 ℃, dropwise adding 620mL of ethynylmagnesium chloride tetrahydrofuran solution (1.1mol, 1.1eq), stirring for 30min after dropwise adding, adding ammonium chloride aqueous solution for quenching, layering, washing the organic phase once with water to prepare a compound (III-4) solution, and directly putting the compound (III-4) solution into the next reaction.
Putting the solution of the compound (III-4) into an autoclave, adding 2g of 5% Pd/C, replacing with hydrogen, adjusting the pressure to 0.2MPa, reacting for 10h, discharging, filtering, and putting the filtrate which is the solution of the compound (IV-4) into the next reaction.
Adding 358.3g of L-dibenzoyltartaric acid (1.0mol, 1.0eq) and 300mL of isopropanol into the solution of the compound (IV-4), heating to 70 ℃, stirring for 2h, cooling to 10-20 ℃, filtering, adding 500mL of isopropanol into the filter cake, and pulping for 3h at 20-30 ℃. After the pulping is finished, filtering to obtain a filter cake, adding 500mL of methyl tert-butyl ether and 300mL of 5M sodium hydroxide solution, stirring for 30min, demixing, and taking an organic phase. 350mL of 1, 4-dioxane solution of 4M hydrogen chloride is added into the organic phase, the mixture is stirred for 1 hour, filtered, and the filter cake is dried to obtain 106.2g of white solid, namely the compound (V-4), wherein the yield is 80.7%, the purity is 99.5%, and the ee value is 99.2%. Compound nuclear magnetic data are as follows:1H NMR(400MHz,D2O):δ3.79(m,1H),δ2.85(s,1H),δ1.14(m,1H),δ0.51(m,4H)；13C NMR(400MHz,D2O):δ74.7，δ74.2，δ44.7，δ10.6，δ1.6。
example 5:
under nitrogen atmosphere, 70.1g of cyclopropane formaldehyde (1.0mol, 1.0eq) and 133.4g of (R) -1-phenylethylamine (1.1mol, 1.1eq) are added into a reaction bottle, dissolved in 1000g of toluene, heated to 100-105 ℃, reacted for 18 hours, cooled to 10-20 ℃, added with 200g of 0.1M hydrochloric acid and washed for 1 time, added with 100g of anhydrous magnesium sulfate in the organic phase, dried and filtered to prepare a compound (II) solution, and the compound (II) solution is directly subjected to the next reaction.
And (3) cooling the toluene solution of the compound (II) to 60 ℃, dropwise adding 667mL of n-butyl magnesium bromide tetrahydrofuran solution (1.2mol, 1.2eq), stirring for 30min after dropwise adding, adding an ammonium chloride aqueous solution for quenching, layering, washing an organic phase once with water to prepare a compound (III-5) solution, and directly putting the compound (III-5) into the next reaction.
Putting the solution of the compound (III-5) into an autoclave, adding 2g of 5% Pd/C, replacing with hydrogen, adjusting the pressure to 0.2MPa, reacting for 10h, discharging, filtering, and putting the filtrate which is the solution of the compound (IV-5) into the next reaction.
Adding 228.3g of (S) -mandelic acid (1.5mol, 1.5eq) and 300mL of isopropanol into the solution of the compound (IV-4), heating to 70 ℃, stirring for 2h, cooling to 10-20 ℃, filtering, adding 500mL of isopropanol into a filter cake, and pulping for 3h at 20-30 ℃. After the pulping is finished, filtering to obtain a filter cake, adding 500mL of methyl tert-butyl ether and 300mL of 5M sodium hydroxide solution, stirring for 30min, demixing, and taking an organic phase. 350mL of 1, 4-dioxane solution of 4M hydrogen chloride is added into the organic phase, the mixture is stirred for 1 hour, filtered, and the filter cake is dried to obtain 144.4g of white solid, namely the compound (V-5), wherein the yield is 88.2%, the purity is 99.2%, and the ee value is 99.3%. Compound nuclear magnetic data are as follows:1HNMR(400MHz,D2O):δ2.1(m,1H),δ1.54(m,2H),δ1.32(m,2H),δ1.27(m,2H)，δ0.74(t,3H),δ0.67(m,1H),δ0.28(m,4H)；13C NMR(400MHz,D2O):δ59.8，δ30.5，δ27.7，δ22.5，δ15.7，δ12.8，δ2.8。
the above description is only for the preferred embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention are within the scope of the present invention.
Claims (9)
1. A synthetic method of chiral amine hydrochloride containing cyclopropyl is characterized by comprising the following synthetic steps:
step 1) Compound (I)
) Cyclopropanecarboxaldehyde as initial material is condensed with (R) -1-phenylethylamine to prepare compound (A)
) Compound (A) to (B)
) Reacting with (R) -1-phenylethylamine in a solvent at 50-110 ℃, and performing post-treatment to obtain a compound (II) or a solution thereof, wherein the solvent is tetrahydrofuran, toluene,Any one or more of 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane and dichloromethane, wherein the molar ratio of the cyclopropanecarboxaldehyde to the (R) -1-phenylethylamine is 1: 1-3;
step 2) Compound (I)
) The solution reacts with the Grignard reagent solution at the temperature of-50 to 100 ℃, and the compound (III) or the solution thereof is prepared by post treatment, wherein the compound (III)
) And the mole ratio of the Grignard reagent is 1: 1-10;
step 3) reacting the solution of the general formula compound (III) at 0-100 ℃ and 0.2-10 MPa in hydrogen atmosphere under the catalysis of a catalyst, and performing post-treatment to prepare a general formula compound (IV) or a solution thereof;
step 4), adding a resolving agent and a solvent into the compound (IV) with the general formula or a solution thereof for resolution, and then carrying out post-treatment to convert the compound into hydrochloride to prepare the compound (V) with the general formulaS) Mandelic acid, (iii)S) -any one or more of acetyl mandelic acid, L-dibenzoyl tartaric acid, L-tartaric acid, said solvent being any one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, water;
the Grignard reagent is methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, vinyl magnesium chloride, vinyl magnesium bromide, ethynyl magnesium chloride, ethynyl magnesium bromide, n-propyl magnesium chloride, n-propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, and the corresponding R group is methyl, ethyl, vinyl, ethynyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
2. The method for synthesizing chiral amine hydrochloride containing cyclopropyl according to claim 1, wherein in step 1), cyclopropanecarbaldehyde and (A), (B) and (C) are usedR) A compound (1-phenylethylamine) is prepared by a reaction at a molar ratio of 1: 1-1.5, a solvent is toluene and a reaction temperature of 80-110 ℃
）。
3. The synthesis method of chiral amine hydrochloride containing cyclopropyl according to claim 1, wherein in the step 1), the compound(s) (A) is (are) prepared by post-treatment
) Or a solution, and carrying out the next reaction.
4. The method for synthesizing chiral amine hydrochloride containing cyclopropyl according to claim 1, wherein in the step 2), the reaction temperature is-20 to 60 ℃, (C) compound
) And the mole ratio of the Grignard reagent is 1:1 to 1.5.
5. The method for synthesizing chiral amine hydrochloride containing cyclopropyl according to claim 1, wherein in step 2), the compound of formula (I), (II) is prepared by post-treatment
I) Or a solution, and carrying out the next reaction.
6. The method for synthesizing chiral amine hydrochloride containing cyclopropyl according to claim 1, wherein in the step 3), the reaction temperature is 30-60 ℃ and the hydrogen pressure is 0.5-1 Mpa.
7. The method for synthesizing chiral amine hydrochloride containing cyclopropyl according to claim 1, wherein the catalyst is any one or more of palladium carbon, rhodium carbon, platinum carbon and platinum oxide.
8. The method for synthesizing chiral amine hydrochloride containing cyclopropyl according to claim 7, wherein in step 3), the catalyst is palladium on carbon.
9. The method for synthesizing chiral amine hydrochloride containing cyclopropyl according to claim 1, wherein in the step 4), the resolving agent is (A)S) -mandelic acid in isopropanol as solvent, resolved and converted into the hydrochloride to obtain compound (V).
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| CN1989097A (en) * | 2004-07-22 | 2007-06-27 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of a diastereomerically enriched compound |
| CN102171205A (en) * | 2008-07-31 | 2011-08-31 | 百时美施贵宝公司 | Pyrazinone modulator of corticotropin-releasing factor receptor activity |
| CN105017082A (en) * | 2015-07-31 | 2015-11-04 | 上海皓元化学科技有限公司 | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate |
| CN105237406A (en) * | 2015-10-14 | 2016-01-13 | 湖南华腾制药有限公司 | Synthesis method of (R)-(-)-1-methyl-3-amphetamine |
| CN106831538A (en) * | 2017-01-22 | 2017-06-13 | 苏州楚凯药业有限公司 | The preparation method of tropsch imatinib intermediate |
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| US20200031753A1 (en) * | 2017-04-06 | 2020-01-30 | Boehringer Ingelheim International Gmbh | Cyclopropyl alkyl amines and process for their preparation |
| EP3867224A1 (en) * | 2018-10-18 | 2021-08-25 | Boehringer Ingelheim International GmbH | Scalable synthesis of optically active 1-cyclopropylalkyl-1-amines |
| CN112552184B (en) * | 2020-12-18 | 2022-05-10 | 诚达药业股份有限公司 | Synthetic method of cyclopropyl-containing chiral amine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1989097A (en) * | 2004-07-22 | 2007-06-27 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of a diastereomerically enriched compound |
| CN102171205A (en) * | 2008-07-31 | 2011-08-31 | 百时美施贵宝公司 | Pyrazinone modulator of corticotropin-releasing factor receptor activity |
| CN105017082A (en) * | 2015-07-31 | 2015-11-04 | 上海皓元化学科技有限公司 | Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate |
| CN105237406A (en) * | 2015-10-14 | 2016-01-13 | 湖南华腾制药有限公司 | Synthesis method of (R)-(-)-1-methyl-3-amphetamine |
| CN106831538A (en) * | 2017-01-22 | 2017-06-13 | 苏州楚凯药业有限公司 | The preparation method of tropsch imatinib intermediate |
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| WO2022126942A1 (en) | 2022-06-23 |
| AU2021404731B2 (en) | 2023-03-30 |
| AU2021404731A1 (en) | 2022-07-28 |
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