CN110577472A - Preparation method of (1R,3S) -3-amino-1-cyclopentanol hydrochloride - Google Patents
Preparation method of (1R,3S) -3-amino-1-cyclopentanol hydrochloride Download PDFInfo
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
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- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C235/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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Abstract
The invention provides a preparation method of (1R,3S) -3-amino-1-cyclopentanol hydrochloride. Synthesizing a target compound by a chiral induction method, specifically, reacting cheap chiral hydroxy acid serving as a raw material with hydroxylamine to generate chiral N-acyl hydroxylamine A. The N-acylhydroxylamine A and cyclopentadiene produce asymmetric Diels-Alder reaction to obtain azabicyclic addition compound, and the product is recrystallized to purify to obtain single optical isomer B. And (3) carrying out catalytic hydrogenation reaction on the compound B, and carrying out ring opening to obtain a compound C, wherein the used catalyst is Pd/C. The compound C is subjected to hydrolysis reaction and salification to obtain a target product (1R,3S) -3-amino-1-cyclopentanol hydrochloride (namely, salified)Compound D).
Description
Technical Field
The invention belongs to the technical field of medicines.
Background
AIDS is a very harmful infectious disease caused by infection with the HIV virus. Bictegravir (formula 1) is a drug developed by Gilead corporation for the treatment of HIV, and Biktarvy, a compound drug consisting of Bictegravir and several other drugs, was approved for sale in the united states in 2018.
formula 1. structure of Bictegravir.
(1R,3S)-3-amino-1-cyclopentanol hydrochloride is an important intermediate for the synthesis of Bictegravir, as reported in the literatureWO2015195656A2、CN106470975A、Bioorg. Med. Chem. Lett. 2000，p1917-1920Its synthetic method is reported, and can be classified into the following three methods: chiral source synthesis, enzymatic resolution and chemical resolution.
The chiral source synthesis is to obtain a product (1R,3S) -3-amino-1-cyclopentanol by using (-) Vince Lactam as a raw material through hydrogenation, amino protection, Grignard reaction, Baeyer-Villiger oxidation and hydrolysis, and salifying to obtain hydrochloride.
The other strategy of chiral source synthesis is to obtain a target product by taking (1S,4R) -cis-4-acetoxyl-2-cyclopentene-1-alcohol as a raw material and carrying out allyl substitution reaction, hydrogenation and deprotection reaction under the catalysis of palladium.
The enzyme resolution method is thatcis-N-Boc-3-amino-1-pentanolThe (1S,3R) -isomer in the raceme is selectively esterified with glutaric anhydride under the enzyme catalysis, then separated from the unreacted (1R,3S) -isomer by a method of salifying with alkali, and the glutarate of the (1S,3R) -isomer obtained after separation is hydrolyzed to obtain the (1S,3R) -3-amino-1-cyclopentanol hydrochloride.
The chemical resolution method is that racemic modification of cis-N-Boc-3-amino-1-pentanol is reacted with chiral acid under heating condition to remove Boc protecting group and form salt, and the salt is separated by recrystallization in proper solvent to obtain the required (1S,3R) -isomer by utilizing the solubility difference of the two salt isomers.
Disclosure of Invention
In the existing method for preparing (1R,3S) -3-amino-1-cyclopentanol hydrochloride, the chiral source synthesis route is short, the operation is convenient, and the optical purity of the product is high, but the raw materials (-) Vince Lactam and (1S,4R) -cis-4-acetoxyl-2-cyclopentene-1-ol are not easy to obtain and are expensive, and the product obtained by the two raw materials is high in price and has no market competitiveness; in addition, since raw materials are not easily available, it is difficult to ensure mass production and continuous supply of products. Although the chemical resolution method and the enzymatic resolution method can avoid the advantage that raw materials are not easily obtained in the chiral synthesis method, the theoretical resolution yield is 50%, the actual enzymatic resolution yield is about 45%, the chemical resolution yield is only about 30%, the atom economy is poor, the generated three wastes are more, the raw material cost is higher, and the space is reduced.
Therefore, the present invention provides a method for preparing (1R,3S) -3-amino-1-cyclopentanol hydrochloride. The target compound is synthesized by a chiral induction method, specifically, cheap chiral hydroxy acid is used as a raw material to react with hydroxylamine to generate chiral N-acyl hydroxylamine A, and the specific preparation method refers to the Eur. J. Inorg. chem., 2006, 1466-1474 and other documents. The N-acylhydroxylamine A and cyclopentadiene produce asymmetric Diels-Alder reaction to obtain azabicyclic addition compound, and the product is recrystallized to purify to obtain single optical isomer B. And (3) carrying out catalytic hydrogenation reaction on the compound B, and carrying out ring opening to obtain a compound C, wherein the used catalyst is Pd/C. And (3) carrying out hydrolysis reaction on the compound C to obtain a target product (1R,3S) -3-amino-1-cyclopentanol hydrochloride (compound D).
The compound C is hydrolyzed to prepare the compound D by two methods, and the compound D can be hydrolyzed in an acid environment or an alkaline environment. And adding an anhydrous hydrogen chloride methanol solution into the compound C, heating to about 50 ℃ for reaction, removing residual hydrogen chloride and methanol through post-treatment after the raw materials disappear, and washing, filtering and drying the residue to obtain a compound D.
Compound C may also be hydrolyzed in a basic environment. Adding sodium methoxide and methanol into the compound C, stirring, dissolving, heating to about 35 ℃ for reaction, quenching the reaction after the raw materials disappear, and then adding di-tert-butyl dicarbonate for reaction. After the reaction is completed, the (1R,3S) -3-amino-1-cyclopentanol is obtained through post-treatment, and then the compound D is prepared by dissolving the compound in a solvent and introducing hydrogen chloride gas. Through tests, the compound C is hydrolyzed in another alkaline environment, tetrahydrofuran and lithium hydroxide solution are added into the compound C, the mixture is heated to 50 ℃ for reaction, and after the reaction is finished, di-tert-butyl dicarbonate is added for reaction. After the reaction is completed, carrying out post-treatment to obtain (1S,3R) -3-hydroxycyclopentyl-1-tert-butyl carbamate, dissolving the tert-butyl carbamate in a solvent, and introducing hydrogen chloride gas to prepare a compound D.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Synthesis of (R) -N, 2-dihydroxy-2-phenylacetamide (Compound A1, R1= Ph)
Reference eur. j. inorg. chem., 2006, 1466-1474.
Example 2
(R) -N, 2-dihydroxypropanamide (Compound A2, R1= CH)3) Synthesis of (2)
Reference J. Am. chem. Soc., 1917, 39(4), p 659-668.
Example 3
Synthesis of (R) -1- ((1R,4S) -3-oxa-2-aza-bicyclo [2.2.1] pent-5-en-2-yl l) -2-hydroxy-2-acetophenone (Compound B1, R1= Ph)
16.7g A1 and 60mL of methanol are added into a reaction bottle, stirred and dissolved completely, cooled to about minus 10 ℃, added with freshly steamed cyclopentadiene, and added with the aqueous solution of sodium periodate dropwise. And after the reaction is completed, filtering, collecting filtrate, adding saturated sodium bisulfite into the filtrate to quench the reaction, concentrating under reduced pressure to remove methanol, adding ethyl acetate into a water phase to extract twice, combining extract liquor, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain 19.8g of a product, wherein the yield is 85.7%. Dr =3.5/1 of the product, and a single configuration product can be obtained after recrystallization.
Example 4
Synthesis of (R) -1- ((1R,4S) -3-oxa-2-aza-bicyclo [2.2.1] pent-5-en-2-yl l) -2-hydroxy-2-acetophenone (Compound B1, R1= Ph)
Adding 5g A1, 50mL tetrahydrofuran, proper amount of cuprous chloride and pyridine into a reaction bottle, adding fresh cyclopentadiene, and stirring uniformly. Oxygen or air is continuously introduced into the reaction bottle until the reaction is completed. Adding 5% sodium ethylene diamine tetracetate solution into the reaction mixture, fully stirring, standing, filtering, concentrating the filtrate to evaporate tetrahydrofuran, extracting the aqueous phase with ethyl acetate for three times, combining the extract liquor, drying with anhydrous sodium sulfate, filtering, concentrating to obtain 4.2g of a product, wherein the yield is 52.8%, and dr = 1.5/1.
Example 5
Synthesis of (R) -1- ((1R,4S) -3-oxa-2-aza-bicyclo [2.2.1] pent-5-en-2-yl) -2-hydroxy-1-propanone (Compound B2, R1= CH 3)
10.5g A2 ml and 30 ml of methanol are added into a reaction bottle, stirred and dissolved completely, cooled to 0 ℃, added with freshly distilled cyclopentadiene and added with an aqueous solution of sodium periodate dropwise. And after the reaction is completed, filtering, collecting filtrate, adding saturated sodium bisulfite into the filtrate to quench the reaction, concentrating under reduced pressure to remove methanol, adding ethyl acetate into a water phase to extract twice, combining extract liquor, drying by anhydrous sodium sulfate, filtering, and concentrating to obtain 13.7g of a product with the yield of 81.1%. Dr =4/1 of the product, and recrystallization can obtain a product with a single configuration.
Example 6
Synthesis of (R) -1- ((1R,4S) -3-oxa-2-aza-bicyclo [2.2.1] pent-5-en-2-yl) -2-hydroxy-1-propanone (Compound B2, R1= CH 3)
Reference Tetrahedron lett, 1995, 36(41), p.7535-. 15.5g A2 and 100 ml methanol and freshly distilled cyclopentadiene were added to the reaction flask and the temperature was reduced to-78 ℃ under nitrogen. And (2) dropwise adding a methanol solution of tetraethyl ammonium periodate, heating to-10 ℃ for reaction after dropwise adding, heating to 25 ℃ after reaction, adding saturated sodium bisulfite for quenching reaction, concentrating under reduced pressure to remove methanol, extracting the water phase with ethyl ester for three times, combining the extract liquor, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 21.3g of a product, wherein the yield is 85.7%, and the dr of the product is = 8/1.
Example 7
Synthesis of (R) -2-hydroxy-N- ((1S,3R) -3-hydroxycyclopentyl) -2-phenylacetamide (Compound C1, R1= Ph)
Adding 2.0g B1, 50mL methanol, 0.2g 10% Pd/C into the hydrogenation kettle, closing the kettle cover, converting the air in the kettle with nitrogen, converting the nitrogen in the kettle with hydrogen, filling hydrogen to 0.5MPa, and heating to 80 ℃ for reaction. After the reaction is finished, removing residual gas in the kettle, after nitrogen conversion, opening the kettle cover, taking out reaction liquid in the kettle, filtering, concentrating to obtain a product, and recrystallizing to obtain a white solid with the yield of 58 percent, wherein the white solid is 1.16 g. The product structure is detected correctly by nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrum, and the detection result is as follows:
1H-NMR(CD3OD, 400MHz): δppm 7.28-7.44(m,5H), 4.97(s, 1H), 4.25-4.29(m, 2H), 2.10-2.13(m, 1H), 2.01-2.08(m, 1H), 1.68-1.86(m, 3H), 1.50-1.62(m, 1H)；
13C-NMR(CD3OD, 100MHz): δppm 173.01， 140.40，127.97， 127.68， 126.58， 49.03， 41.15， 33.31，30.58；
HRMS theoretical value: 236.1281(M +1), detection value: 236.1279(M + 1).
Example 8
Synthesis of (R) -2-hydroxy-N- ((1S,3R) -3-hydroxycyclopentyl) -2-phenylacetamide (Compound C1, R1= Ph)
Adding 2.6g B1, 50mL of methanol and 0.4g of 10% Pd/C into a hydrogenation kettle, closing the kettle cover, converting the air in the kettle by using nitrogen, converting the nitrogen in the kettle by using hydrogen, filling hydrogen into the hydrogenation kettle to 3.0MPa, and heating to 25 ℃ for reaction. After the reaction is finished, removing residual gas in the kettle, replacing the residual gas with nitrogen, opening the kettle cover, taking out reaction liquid in the kettle, filtering, concentrating to obtain a product, and recrystallizing to obtain a white solid with the yield of 70.8 percent, wherein the white solid is 1.87 g.
Example 9
Synthesis of (R) -2-hydroxy-N- ((1S,3R) -3-hydroxycyclopentyl) propionamide (Compound C2, R1= CH 3)
1.74g B2, 50mL of methanol and 0.4g of 10% Pd/C were added to the hydrogenation reactor, the lid was closed, the atmosphere in the reactor was changed with nitrogen, the atmosphere in the reactor was changed with hydrogen, and hydrogen was charged to 2.0MPa at 0 ℃ to react. After the reaction is finished, removing residual gas in the kettle, after nitrogen conversion, opening the kettle cover, taking out reaction liquid in the kettle, filtering, concentrating to obtain a product, and recrystallizing to obtain a white solid with the yield of 74.1 percent.
example 10
Synthesis of (R) -2-hydroxy-N- ((1S,3R) -3-hydroxycyclopentyl) propionamide (Compound C2, R1= CH 3)
Adding 2.07g B2, 50mL methanol, 0.05g 10% Pd/C into the hydrogenation kettle, closing the kettle cover, converting the air in the kettle with nitrogen, converting the nitrogen in the kettle with hydrogen, filling hydrogen to 3.0MPa, and heating to 55 ℃ for reaction. After the reaction is finished, removing residual gas in the kettle, after nitrogen conversion, opening the kettle cover, taking out reaction liquid in the kettle, filtering, concentrating to obtain a product, and recrystallizing to obtain a white solid with the yield of 74.9 percent, wherein the white solid is 1.58 g.
Example 11
Synthesis of (1R,3S) -3-aminocyclopentanol hydrochloride (Compound D)
Example 1: 1.2g C1, 10mL of anhydrous hydrogen chloride methanol solution is added into a reaction bottle, the reaction is carried out by heating to 50 ℃, after the raw materials disappear, the residual hydrogen chloride and methanol are removed by decompression concentration, the residue is washed by methyl tert-butyl ether slurry, and after filtration and drying, 0.43g of white solid D is obtained with the yield of 61.4%. The nuclear magnetic hydrogen spectrum detection result shows that the product structure is correct.
1H-NMR(CDCl3, 400MHz): δppm 4.13-4.19(m,1H), 3.43-3.48 (m, 1H), 2.55(brs, 3H), 1.68-1.82(m, 4H), 1.46-1.55(m, 2H)。
Example 12
Synthesis of (1R,3S) -3-aminocyclopentanol hydrochloride (Compound D)
Adding 1.5g C2, 20mL anhydrous hydrogen chloride methanol solution into a reaction bottle, reacting at 25 ℃ until the raw material disappears, concentrating under reduced pressure to remove residual hydrogen chloride and methanol, washing the residue with methyl tert-butyl ether slurry, filtering, and drying to obtain white solid D0.82g with a yield of 68.9%.
example 13
Synthesis of tert-butyl (1S,3R) -3-hydroxycyclopentyl-1-carbamate
Adding 1.2g C1, sodium methoxide and 10mL of methanol into a reaction bottle, stirring, dissolving, heating to 35 ℃ for reaction, adding ice water to quench the reaction after the raw materials disappear, and then adding di-tert-butyl dicarbonate for reaction. After the reaction is completed, the methanol is distilled off, the water phase is extracted by methyl tert-butyl ether, the product is obtained after the extract liquid is dried, filtered and concentrated, the weight is 0.77g after the product is placed and solidified, and the yield is 75.0%. The nuclear magnetic hydrogen spectrum detection result shows that the product structure is correct.
1H-NMR(CDCl3, 400MHz): δppm 5.15(brs,1H), 4.32-4.33 (m, 1H), 4.0(brs, 1H), 2.67(brs, 1H),1.94-2.06(m, 2H), 1.70-1.77(m, 3H), 1.57-1.60(m, 1H), 1.41(s, 9H)。
Example 14
Synthesis of tert-butyl (1S,3R) -3-hydroxycyclopentyl-1-carbamate
Adding 2.7g C2 tetrahydrofuran into a reaction bottle, stirring and dissolving completely, then adding 2M lithium hydroxide solution, heating the mixed solution to 50 ℃ for reaction, and adding di-tert-butyl dicarbonate for reaction after the hydrolysis reaction is completely finished. Adding methyl tert-butyl ether for extraction, drying, filtering and concentrating the extract to obtain the product with the weight of 2.33g and the yield of 73.7 percent.
Example 15
Synthesis of (1R,3S) -3-aminocyclopentanol hydrochloride (Compound D)
Adding 4.2g of (1S,3R) -3-hydroxycyclopentyl-1-carbamic acid tert-butyl ester and 30 ml of methyl tert-butyl ether into a reaction bottle, stirring and dissolving completely, cooling to 0 ℃, introducing hydrogen chloride gas until the reaction is complete, filtering, collecting a filter cake, and drying to obtain 2.16g of white solid with the yield of 75.0%.
Claims (7)
1. A process for the preparation of (1R,3S) -3-amino-1-cyclopentanol hydrochloride (compound D), characterized in that compound C is obtained by hydrolysis in an acidic or basic environment,
Wherein R1 is phenyl or methyl.
2. The process of claim 1, compound C is hydrolyzed in an acidic environment to form compound D, wherein the acidic environment is a solution of anhydrous hydrogen chloride in methanol.
3. The process of claim 1, wherein compound C is hydrolyzed in alkaline environment to obtain compound D, wherein the alkaline environment is sodium methoxide, methanol, di-tert-butyl dicarbonate, and hydrogen chloride gas is introduced to form salt.
4. The method of claim 1, wherein compound C is hydrolyzed in an alkaline environment to form compound D, wherein the alkaline environment is lithium hydroxide, tetrahydrofuran, di-tert-butyl dicarbonate, and hydrogen chloride gas is introduced to form the salt.
5. The process according to claim 1, a process for the preparation of compound C, characterized in that compound B is prepared by catalytic hydrogenation
Prepared, wherein R1 is phenyl or methyl.
6. The process as claimed in claim 5, wherein the catalyst is Pd/C.
7. A compound of the general formula C,
Wherein R1 is phenyl or methyl.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109651178A (en) * | 2018-12-24 | 2019-04-19 | 广东莱佛士制药技术有限公司 | A kind of preparation method of (1R, 3S) -3- Aminocyclopentanol hydrochloride |
| CN113214251A (en) * | 2021-04-30 | 2021-08-06 | 湖北丽益医药科技有限公司 | Preparation method of tadalafil intermediate impurity |
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| US20040106794A1 (en) * | 2001-04-16 | 2004-06-03 | Schering Corporation | 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
| CN102633657A (en) * | 2012-03-30 | 2012-08-15 | 兰州中泰和生物科技有限公司 | Preparation method of cis-3-amino-cyclopentanol hydrochloride |
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| US20040106794A1 (en) * | 2001-04-16 | 2004-06-03 | Schering Corporation | 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
| CN102633657A (en) * | 2012-03-30 | 2012-08-15 | 兰州中泰和生物科技有限公司 | Preparation method of cis-3-amino-cyclopentanol hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651178A (en) * | 2018-12-24 | 2019-04-19 | 广东莱佛士制药技术有限公司 | A kind of preparation method of (1R, 3S) -3- Aminocyclopentanol hydrochloride |
| CN113214251A (en) * | 2021-04-30 | 2021-08-06 | 湖北丽益医药科技有限公司 | Preparation method of tadalafil intermediate impurity |
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