cas 334618-23-4, (R)-3-Piperidinamine dihydrochloride

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Preparation of (R)-3-aminopiperidine by resolution with optically active cyclic phosphoric acids
(R)-3-aminopiperidine ((R)-APD), a key intermediate for alogliptin, trelagliptin, and linagliptin, was successfully resolved from racemic 3-aminopiperidine with an enantiomerically pure resolving agent, namely, (R)-4-(2-chlohydroxy-1.3.2-dioxaphosphorinane 2-oxide ((R)-CPA), via diastereomeric salt formation. By this resolution approach, (R)-3-aminopiperidine was obtained in 99.5% yield with 99.6%e.e.
Sun, Yujuan,Hu, Beibei,Jing, Yongshuai,Wu, Jialiang,Zhou, Maochao,Chen, Meng,Hao, Feifei,Zhang, Chen,Sun, Fengxia
p. 379 - 384
(2021)
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Synthesis method of trelagliptin intermediate
The invention belongs to the technical field of medicines, and particularly relates to a synthesis method of a trelagliptin intermediate (R)-3-aminopiperidine dihydrochloride. The synthesis method specifically comprises the following steps: 1) reducing carbonyl of a compound shown as a formula I in an organic solvent A by using a reducing agent to prepare a compound shown as a formula II; 2) splitting the compound shown in the formula II in an organic solvent B through a chiral reagent to prepare a compound shown in a formula III; and 3) removing the benzyl of the compound shown by the formula III by palladium on carbon to obtain the (R)-3-aminopiperidine dihydrochloride. The (R)-3-aminopiperidine dihydrochloride prepared by the method has high yield and purity, the HPLC purity is higher than 98.16%, and the optical purity is higher than 98.92%; and the synthesis method has the advantages of low price of initial raw materials, facilitation of reduction of industrial cost, short synthesis process route, mild reaction conditions and easy industrial realization.
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(2021/07/17)

Preparation method and application of (R)-3-aminopiperidine dihydrochloride
The invention provides a preparation method and application of (R)-3-aminopiperidine dihydrochloride. The preparation method comprises the following steps: obtaining (S)-1, 5-dichloro-2-pentanol through the reaction of (S)-epichlorohydrin and 2-chloroethyl magnesium bromide; carrying out an intramolecular cyclization reaction in the presence of an alkaline substance to generate (S)-5-chloro-1, 2-epoxypentane; enabling the (S)-1-benzylamino-5-chloro-2-epoxypentane to react with benzylamine to generate (S)-1-benzylamino-5-chloro-2-pentanol; then obtaining (S)-1-benzyl-3-hydroxypiperidine throughan intramolecular ring closing reaction of (S)-1-benzylamino-5-chloro-2-pentanol; continuing to react with the sulfonyl chloride compound to obtain (R)-1-benzyl-3-sulfonyloxy piperidine; further reacting with benzylamine to obtain (R)-1-benzyl-3-benzylamino piperidine; and finally, under the action of a palladium catalyst, removing benzyl through hydrogenation, thus obtaining the product (R)-3-aminopiperidine dihydrochloride. The preparation method has the advantages of few side reactions, high yield, good product quality, convenient purification, easily available raw materials, low price, mild reaction conditions, high safety, environmental protection, simplicity, practicality, and suitableness for industrial batch production.
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(2020/12/08)

Synthesis method of chiral 3-aminopiperidine and derivatives of 3-aminopiperidine
The invention relates to a synthesis method of chiral 3-aminopiperidine and derivatives of 3-aminopiperidine. According to the synthesis method, R (or S)-piperidine-3-ethyl formate-L (or D)-tartrate is subjected to a hydrazinolysis reaction after being subjected to benzyl protection, and R or S-1-benzyl-3-aminopiperidine is obtained through azidation and Curtius rearrangement. R or S-1-benzyl-3-aminopiperidine is subjected to debenzylation, R or S-3-aminopiperidine can be obtained, R or S-1-benzyl-3-aminopiperidine is subjected to 3-t-butyloxycarboryl protection and debenzylation in sequence,R or S-(3-t-butyloxycarborylamino) piperidine can be obtained, and corresponding salts of R or S-3-aminopiperidine can be obtained through hydrolyzing deprotection of R or S-(3-t-butyloxycarborylamino) piperidine under the acidic condition. The synthesis method of chiral 3-aminopiperidine and the derivatives of 3-aminopiperidine is low in cost, facilitates industrialization and has high optical purity.
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(2019/09/17)

Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases
Chiral N-heterocyclic molecules and in particular compounds with an amino functional group such as 3-aminopiperidine are valuable intermediates for the production of a large number of bioactive compounds with pharmacological properties. In this paper, the synthesis of both enantiomers of 3-amino-1-Boc-piperidine by amination of the prochiral precursor 1-Boc-3-piperidone using immobilized ω-transaminases (TAs-IMB), isopropylamine as amine donor and pyridoxal-5’-phosphate (PLP) as cofactor is described. Compared to other methods, the present approach affords the target compound in just one step with high yield and high enantiomeric excess starting from a commercial substrate. The reaction was carried out by using different commercially available immobilized enzymes, evaluating the catalytic activity and the enantioselectivity under different experimental conditions. Re-use of the most efficient enzyme was performed both in batch and in a semi-continuous system. The selected biocatalyst showed good stability under the reaction conditions providing consistent results in terms of conversion and enantiomeric excess after several cycles. The reported results may be of practical interest in view of the development of this sustainable approach to an industrial scale.
Petri, Antonella,Colonna, Valeria,Piccolo, Oreste
p. 60 - 66
(2019/01/28)

Synthetic process of anti-hyperglycemic drug intermediate R-3-amino-piperidine dihydrochloride
The invention relates to a synthetic process of an anti-hyperglycemic drug intermediate R-3-amino-piperidine dihydrochloride. The synthetic process comprises the steps: using inexpensive L-glutamic acid as a starting material, and performing esterification, amino protection, reduction, hydroxyl protection, substitution, cyclization and removal of protecting groups for amino groups so as to obtainthe R-3-amino-piperidine dihydrochloride. Compared with the prior art, the synthetic process has cheap and easily available raw materials, good selectivity, good atomic economy, high total yield and mild reaction conditions, and is suitable for industrial production.
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Paragraph 0072-0075

(2019/11/12)

Method for preparing chiral compound by using intermediate
The invention provides a method for preparing a chiral compound by using an intermediate. The method is characterized by comprising the following steps: (a) enabling a compound II to be contacted witha compound III in a solvent, and refining to obtain a c
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Paragraph 0077; 0080; 0081

(2018/11/04)

A methof for preparing (R)- (+) - 3 - amino piperidine dihydrochloride method
The invention discloses a method for preparing (R)-(+)-3-piperidinamine dihydrochloride by using a resolution method, which belongs to the field of racemic compound resolution. The method is specifically implemented by taking 1-2 equivalent amounts of (+)-4-(2-chlorphenyl)-2-hydroxy-5 and 5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane as resolution agents through enabling the resolution agents to react with racemic 3-aminopiperdine in an alcohol-water solution, so that salt coagulation is realized; reducing the temperature of the obtained object so as to separate out solids, and carrying out dissociation on the solids, so that optical pure (R)-(+)-3-aminopiperidinedihydrochloride is obtained; and carrying out dissociation on mother liquor so as to recover (S)-(-)-3-aminopiperidinedihydrochloride, carrying out racemization on the (S)-(-)-3-aminopiperidinedihydrochloride, and recycling the obtained product. The method is simple in operation, and a resolution reagent can be recycled, therefore, the method is suitable for industrial production.
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Paragraph 0037; 0040

(2018/02/04)

Compound I and (R)- 3 - amino piperidine hydrochloride II, its preparation method and its application in the synthesis of advantage geleg sandbank
The invention discloses a preparation method of 3-aminopiperidine and its derivative with optical activity and an application of the compound and its derivative in synthesis of a dipeptidyl peptidase-IV inhibitor Linagliptin. According to the preparation
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(2017/10/22)

A process for preparing (R)- or (S)- 3 - amino piperidine-hydrochloride
The invention discloses a method for preparing (R)-or(S)-3-aminopiperidine dihydrochloride. The method includes the steps of taking N-Boc-3-piperidone as the raw material, making N-Boc-3-piperidone have a condensation reaction with enantiomerically pure (S)-or(R)-tert-butanesulfinyl amide under the existence of the catalytic amount of pyrrolidine, then conducting low-temperature reduction through a reducing agent, obtaining an enantiomerically pure intermediate after ethyl alcohol/heptane recrystallization, and obtaining (R)-or(S)-3-aminopiperidine dihydrochloride after removing the protection of Boc and tert-butanesulfinyl amide in hydrochloric acid at the same time.
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Paragraph 0027; 0030; 0031

(2017/08/25)

Application of asymmetric hydrogenation in synthesis of Trelagliptin intermediate
The invention provides a synthetic method of a compound Trelagliptin intermediate represented by a formula (1) (shown in the description). The synthetic method comprises the steps of carrying out a series of reactions on a starting material, namely a compound represented by a formula (1) (shown in the description) so as to finally obtain the compound by the formula (1), namely the Trelagliptin intermediate. Compared with a synthetic method of the Trelagliptin intermediate which comprises more synthetic steps and has a complex synthetic process in the prior art, the synthetic method provided by the invention is simple, feasible, relatively low in cost, relatively high in yield, relatively good in product quality and suitable for large-scale industrial production.
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(2018/09/21)

Intermediate argues a row sandbank R-3-amino piperidine dihydrochloride preparation method
The invention aims to provide a preparation method for an alogliptin intermediate R-3-aminopiperidine dihydrochloride. The method has a brief route and is environmentally friendly and low-cost. A racemic compound 3- piperidine carboxamide which is cheap and easy to get is taken as a raw material, and is subjected to Hoffmann rearrangement reaction under the action of 1- fluoronaphthalene, hydrogen peroxide and fluoboric acid, which is similar to acid amides, to obtain 3-aminopiperdine which has one less carbon than the substrate. The method has simple reaction conditions, can be implemented at the room temperature, has simple operations in process, and is easy to monitor. The solvents are an ethanol-water mixture, and are low-cost and environmentally friendly. The carbon-lessened product 3-aminopiperidine is acidized and salified by concentrated hydrochloric acid. The hydrochloride is separated and salified by D-tartaric acid to obtain the target product R-3-aminopiperidine dihydrochloride. The chirality purity is high. The ee value is more than 99.5%. The reaction overall yield can reach 89%-93%. The cost is low. The method is suitable for industrial mass production.
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Paragraph 0020

(2018/02/04)

(R) - 3-amino-piperidine dihydrochloride preparation method
The invention discloses a method for preparing (R)-3-amino piperidine hydrochloride. D-glutamic acid is taken as a starting material, and the (R)-3-amino piperidine hydrochloride is obtained by reaction in the following five steps: (1) hydroxyl esterification and amido Boc protection; (2) ester reduction; (3) hydroxyl activation; (4) cyclization; (5) amino Boc removal protection. The preparation method disclosed by the invention is short in synthetic route and low in cost, and industrial production can be achieved.
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Paragraph 0043-0045

(2017/01/09)

Preparation method of medical intermediate R-3-aminopiperidine dihydrochloride
The invention discloses a preparation method of a medical intermediate R-3-aminopiperidine dihydrochloride shown as a formula (I), wherein, the compound is shown as the formula (I) in a specification. The preparation method comprises the following steps: dissolving a compound shown in a formula (III) in alcohol, adding a palladium carbon catalyst and a reducing agent ammonium formate, heating the materials and stirring the materials for backflow, and cooling the materials and filtering the materials, concentrating the materials to obtain R-3-aminopiperidine shown as a formula (II); dissolving the compound shown in the formula (II) in a solvent, cooling by cold water, introducing hydrogen chloride gas under vigorous stirring until the solution is acidic, and standing and filtering the product to obtain R-3-aminopiperidine dihydrochloride in the formula (I), wherein the compound shown as the formula (III) is presented in the specification, and the compound shown as the formula (II) is presented in the specification. According to the invention, the easily acquired compound III is taken as the initial raw material, by using a hydrogenation reagent, (R)-3-aminopiperdine can be obtained through one-step catalytic hydrogenolysis, the integral synthesis route reaction is simpler, operation is more convenient, yield can be greatly increased, and the method of the invention is suitable for large-scale production.
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Paragraph 0019

(2016/12/07)

A kind of optical active pharmaceutical process for the preparation of intermediates
The invention relates to a preparation method of an optical active compound, represented by formula I, or a hydrochloride of the optical active compound by taking a compound with optical activity as a starting material. Raw materials of the preparation method are cheap and easily available; no splitting is needed; the whole technological operation is simple and convenient; cost is low; pollution on environment is less; and the preparation method is suitable for industrialized production. In the formula I, n is 1 or 2 or 3.
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Paragraph 0059; 0060

(2016/10/17)

Highly enantioselective synthesis of non-natural aliphatic α-amino acids via asymmetric hydrogenation
By employing a rhodium-Duanphos complex as the catalyst, β-alkyl (Z)-N-acetyldehydroamino esters were smoothly hydrogenated in a highly efficient and enantioselective way. Excellent enantioselectivities together with excellent yields were achieved for a series of substrates. An efficient approach for the synthesis of the intermediate of the orally administered anti-diabetic drugs Alogliptin and Linagliptin in the DPP-4 inhibitor class was also developed.
Ji, Jianjian,Chen, Caiyou,Cai, Jiayu,Wang, Xinrui,Zhang, Kai,Shi, Liyang,Lv, Hui,Zhang, Xumu
supporting information
p. 7624 - 7627
(2015/07/15)

PROCESS FOR THE PREPARATION OF DIPEPTIDYLPEPTIDASE INHIBITORS
Provided is a process for the preparation of linagliptin of Formula I, comprising deprotecting a compound of Formula II wherein R1 and R2 together with the nitrogen to which they are attached form a phthalimido group, wherein the aromatic ring of the phthalimido group is substituted with one or more R3 substituents selected from the group consisting of halogen, alkyi, nitro and amino; or R1 is H and R2 is selected from the group consisting of trialkylsilyl, 2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl, 9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl, diphenylphosphine and sulfonylethoxycarbonyl.
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Paragraph 0128; 0133

(2015/09/23)

PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED 3-AMINOPIPERIDINE
The present invention relates to a process for the preparation of enantiomerically enriched 3-aminopiperidine, and in particular of its R-enantiomer (R)-3-aminopiperidine. The invention also relates to an enantiomerically enriched intermediate of said process and to specific acid-addition salts of 3-aminopiperidine (hereinafter also APIP) that are useful for obtaining a single enantiomer of APIP, and to crystalline (R)-3-aminopiperidine-dihydrochloride-monohydrateand crystalline (S)-3-aminopiperidine-dihydrochloride-monohydrate.
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Page/Page column 31

(2014/09/03)

IMPROVED PROCESS FOR PREPARATION OF PURE LINAGLIPTIN
The present application provides a process for preparation of Linagliptin reacting (R)-piperidine-3-amine of Formula II or an acid addition salt thereof with 1-[(4-methyl- quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine of Formula III in the presence of a suitable base in an inert organic solvent.
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Page/Page column 20

(2013/07/19)

A catalytic version of hypervalent aryl-λ3-iodane-induced Hofmann rearrangement of primary carboxamides: Iodobenzene as an organocatalyst and m-chloroperbenzoic acid as a terminal oxidant
The first catalytic version of hypervalent aryl-λ3- iodane-induced Hofmann rearrangement of primary carboxamides, which probably involves in situ generation of a tetracoordinated bis(aqua)(hydroxy)phenyl- λ3-iodane complex as an active oxidant from a catalytic amount of iodobenzene by the reaction with m-chloroperbenzoic acid in the presence of HBF4 in dichloromethane-water under mild conditions, was developed.
Miyamoto, Kazunori,Sakai, Yuuta,Goda, Shunsuke,Ochiai, Masahito
supporting information; experimental part
p. 982 - 984
(2012/02/04)

PROCESS FOR THE PREPARATION OF A SINGLE ENANTIOMER OF 3-AMINOPIPERIDINE DIHYDROCHLORIDE
A process comprising: (a) reduction of N-acetyl-3-aminopyridine (2): or its salt in the presence of hydrogen and a palladium catalyst deposited on solid support; (b) converting racemic N-acetyl-3-aminopiperidine (3) or its salt produced in step (a) to rac-3-aminopiperidine (rac-4) or its salt; (c) resolution of the racemic 3-aminopiperidine (rac-4) or its salt produced in step (b) with a chiral acid.
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(2012/01/06)

METHOD FOR OPTICAL RESOLUTION OF ALKYLPIPERIDIN-3-YL CARBAMATE AND INTERMEDIATE THEREFOR
Disclosed is a method for optical resolution of an alkylpiperidin-3-yl carbamate, the method including bringing an RS mixture of an alkylpiperidin-3-yl carbamate into contact with an optically active tartaric acid in the presence of a solvent.
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Page/Page column 16

(2010/11/19)

METHOD FOR PRODUCING OPTICALLY ACTIVE 3-AMINOPIPERIDINE OR SALT THEREOF
The present invention relates to a method for producing an optically active 3-aminopiperidine or salt thereof. In the method, a racemic nipecotamide is stereoselectively hydrolyzed to obtain an optically active nipecotamide and an optically active nipecotic acid in the presence of an enzyme source derived from an organism, and then the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by aroylation, Hofmann rearrangement, deprotection of the amino group and further deprotection; or the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by selective protection with BOC, Hofmann rearrangement and further deprotection. It is possible by the present invention to produce an optically active 3-aminopiperidine or salt thereof useful as a pharmaceutical intermediate from an inexpensive and easily available starting material by easy method applicable to industrial manufacturing.
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Page/Page column 20

(2010/05/13)

PREPARATION OF (R)-3-AMINOPIPERIDINE DIHYDROCHLORIDE
Described herein are methods for making chiral derivatives of 3-aminopiperidine, including the production of such derivatives in quantities exceeding 1 kilogram. The chiral 3-aminopiperidine derivatives include (R) -3-aminopiperidine derivatives which may be used to synthesize inhibitors of Dipeptidyl Peptidase IV. (R) -3-Aminopiperidine dihydrochloride is prepared by reducing (R) -3-aminopiperidin-2-one hydrochloride with lithium aluminum hydride. The preparation of (R) -3-aminopiperidin-2-one hydrochloride starting from (R) -methyl-2, 5-diaminopentanoate dihydrochloride or (R) -2, 5-diaminopentanoic acid hydrochloride is also described.
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(2008/06/13)

METHOD FOR PRODUCING 3-AMINOPIPERIDINE DIASTEREOMER
A method for increasing the enantiomeric purity of a desired enantiomer of 3- aminopiperidine comprising: providing a composition containing (i?)-3-arninopiperidine and (jS)-3-aminopiperidine; combining the composition with a resolving agent selected from
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Page/Page column 4-5

(2008/06/13)