阅读说明：本技术 光学纯环氨基醇及其盐的制备方法 (Process for the preparation of optically pure cyclic aminoalcohols and salts thereof ) 是由 岳祥军 王志邦 邹慧 田磊 徐靖坤 江积旺 陈小峰 刘安友 于 2019-01-16 设计创作，主要内容包括：本发明涉及化学制药领域,具体涉及光学纯环氨基醇及其盐的制备方法。所述方法包括：1)水解：化合物(12)经水解得到化合物(13)；2)催化氢化：将步水解骤得到的化合物(13)进行催化氢化得到化合物(1)。<Image he="89" wi="383" file="DEST_PATH_IMAGE002A.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to the field of chemical pharmacy, in particular to a preparation method of optically pure cyclic amino alcohol and salts thereof. The method comprises the following steps: 1) hydrolysis: hydrolyzing the compound (12) to obtain a compound (13); 2) catalytic hydrogenation: and (3) carrying out catalytic hydrogenation on the compound (13) obtained in the hydrolysis step to obtain a compound (1).)

1. A process for preparing an optically pure cyclic amino alcohol of formula (1), comprising:

1) hydrolysis: hydrolyzing the compound (12) to obtain a compound (13);

2) catalytic hydrogenation: the compound (13) obtained in the hydrolysis step is subjected to catalytic hydrogenation to obtain a compound (1).

2. The method according to claim 1, wherein the hydrolysis reaction in the hydrolysis step is hydrolysis under alkaline conditions or acidic conditions;

preferably, the base used for hydrolysis in the hydrolysis step in the hydrolysis reaction under basic conditions is an organic base or an inorganic base, and is, for example, any one, two or more in combination selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium borohydride, potassium borohydride, ethylenediamine, propylenediamine, butylenediamine;

preferably, the acid used for hydrolysis of the hydrolysis reaction in the hydrolysis step under acidic conditions is a mineral acid, such as any one of hydrochloric acid, sulfuric acid, phosphoric acid, or a combination of two or more thereof.

3. The method according to claim 1 or 2, wherein the catalytic hydrogenation reaction in the catalytic hydrogenation step is carried out in the presence of a catalyst selected from the group consisting of platinum-carbon, palladium-carbon, and nickel.

4. The production method according to any one of claims 1 to 3, wherein the catalytic hydrogenation reaction in the catalytic hydrogenation step is carried out in the presence of a hydrogen source which is any one of hydrogen, cyclohexene, and ammonium formate, or a combination of two or more thereof.

5. The process according to any one of claims 1 to 4, wherein the process for the preparation of the optically pure cyclic amino alcohol of formula (1) further comprises the preparation of compound (12) comprising:

the compound (14) and cyclopentadiene are subjected to an oxidative addition reaction to obtain a compound (12).

6. The process of claim 5, wherein the oxidative addition reaction is carried out in the presence of an oxidizing agent selected from the group consisting of periodates, metal halides, combinations of metal halides with pyridine, combinations of metal halides with peroxides and/or pyridine, titanium/vanadates, and combinations of titanium/vanadates with peroxides.

7. The method according to claim 6, wherein the reaction is carried out in an oxygen atmosphere or an oxygen-containing atmosphere when a metal halide salt, a combination of a metal halide salt and pyridine, or a titanium/vanadium acid ester is used.

8. The process according to any one of claims 1 to 7, wherein the process for the preparation of the optically pure cyclic amino alcohol of formula (1) further comprises the preparation of compound (14) comprising:

reacting the compound (15) with phosgene solid and hydroxylamine hydrochloride to obtain a compound (14).

9. The process according to claim 8, wherein the reaction is carried out under alkaline conditions, and the base used in the reaction is preferably an organic base; for example, at least one of triethylamine, N-diisopropylethylamine, N-dimethylaniline, pyridine, 2, 6-lutidine, 2-picoline, 3-picoline and 4-picoline.

10. The process according to any one of claims 1 to 9, further comprising a step of further preparing the compound (1) to obtain an optically pure salt of the cyclic amino alcohol represented by the formula (2), comprising:

reacting the compound (1) with a compound HX to obtain a compound (2); wherein the compound HX is an organic acid or an inorganic acid.

Technical Field

The invention relates to the field of chemical pharmacy, in particular to a preparation method of optically pure cyclic amino alcohol and salts thereof.

Background

Optically pure cyclic amino alcohol (1), (1R,3S) -3-aminocyclopentanol, or a salt thereof (2) is a key intermediate for producing a drug for treating AIDS, Bictegravir (3).

WO2015195656A2 discloses a preparation method of optically pure cyclic amino alcohol (1) and salts thereof (2), which is realized by eight steps of lactam optical resolution, palladium carbon hydrogenation reduction, amino protection, Grignard reagent ring opening, peroxy acid oxidation, alkali hydrolysis, acid deprotection and acid salt formation. Theoretically the first step of the process is only 50% yield; plus protective agent (Boc) used in the subsequent step₂O), Grignard reagent (CH)₃MgBr and peroxy acid (mCPBA) are expensive; the synthesis route is long, and the total yield is low; is not easy for industrialized mass production.

There is therefore a need for improved processes for the preparation of optically pure cyclic amino alcohols ((1R,3S) -3-aminocyclopentanol) or salts thereof.

Disclosure of Invention

In order to solve the above problems, the present invention provides a process for preparing an optically pure cyclic aminoalcohol represented by the formula (1), comprising:

1) hydrolysis: hydrolyzing the compound (12) to obtain a compound (13);

2) catalytic hydrogenation: carrying out catalytic hydrogenation on the compound (13) obtained in the step 1) to obtain a compound (1);

according to the preparation method of the invention, the temperature of the hydrolysis reaction in the hydrolysis step is-20-150 ℃, and preferably 0-100 ℃;

according to the preparation method of the present invention, the hydrolysis reaction in the hydrolysis step is hydrolysis under an alkaline condition or an acidic condition;

according to the preparation method of the invention, the base used for hydrolysis reaction under alkaline condition in the hydrolysis step is organic base or inorganic base, and the base is selected from any one or combination of two or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium borohydride, potassium borohydride, ethylenediamine, propylenediamine and butylenediamine;

according to the production method of the present invention, the acid used for hydrolysis under acidic conditions in the hydrolysis reaction in the hydrolysis step is an inorganic acid such as any one of hydrochloric acid, sulfuric acid, phosphoric acid, or a combination of two or more thereof.

According to the preparation method, the molar ratio of the compound (12) to the used alkali or acid in the hydrolysis step is 1: 1-10; preferably 1: 3-5;

according to the preparation method of the invention, the temperature of the catalytic hydrogenation reaction in the catalytic hydrogenation step is-20 ℃ to 150 ℃, preferably 0 ℃ to 100 ℃, for example, room temperature or 60 ℃ to 70 ℃;

according to the preparation method of the present invention, the solvent used in the catalytic hydrogenation reaction in the catalytic hydrogenation step may be any one of, a combination of two or more of, toluene, o-xylene, m-xylene, p-xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, propionitrile, methyl t-butyl ether, isopropyl ether, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, or a mixture solvent of the above-mentioned solvent having water solubility and water;

according to the preparation method of the present invention, the catalytic hydrogenation reaction in the catalytic hydrogenation step may be carried out in the presence of a catalyst selected from the group consisting of platinum-carbon, palladium-carbon, nickel;

according to the preparation method of the present invention, the catalytic hydrogenation reaction in the catalytic hydrogenation step may be carried out in the presence of a hydrogen source, which may be any one of hydrogen, cyclohexene, and ammonium formate, or a combination of two or more thereof.

According to the invention, the process for the preparation of the optically pure cyclic amino alcohol of formula (1) also comprises the preparation of compound (12) comprising:

the compound (14) and cyclopentadiene are subjected to an oxidative addition reaction to obtain a compound (12).

In the above preparation method, the oxidative addition reaction is a diene addition reaction of the compound (14) after being oxidized by an oxidant and then with cyclopentadiene. The temperature of the oxidation addition reaction is-20 ℃ to 150 ℃, preferably-10 ℃ to 100 ℃, for example, 0 ℃ to 30 ℃;

in the above-mentioned preparation method, the solvent used in the oxidation addition reaction may be any one of, or a combination of two or more of toluene, o-xylene, m-xylene, p-xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, propionitrile, methyl tert-butyl ether, isopropyl ether, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, and isopropanol, or a mixed solvent of the above-mentioned water-miscible solvent and water;

in the above production method, the oxidative addition reaction is carried out in the presence of an oxidizing agent selected from the group consisting of periodate salts, metal halide salts, compositions of metal halide salts and pyridine, compositions of metal halide salts and peroxide and/or pyridine, titanium/vanadate esters, and compositions of titanium/vanadate esters and peroxide;

when a metal halide salt, a combination of a metal halide salt and pyridine, or a titanium/vanadate ester is used, the reaction is carried out in an oxygen atmosphere or an oxygen-containing atmosphere, for example, in an air atmosphere.

Preferably, the oxidative addition step is carried out under the following conditions: sodium periodate, ferric trichloride-hydrogen peroxide, ferric trichloride-tert-butyl hydroperoxide, ferric trichloride-oxygen, ferric trichloride-air, ruthenium trichloride-hydrogen peroxide, ruthenium trichloride-tert-butyl hydroperoxide, ruthenium trichloride-oxygen, ruthenium trichloride-air, nickel chloride-hydrogen peroxide, nickel chloride-tert-butyl hydroperoxide, nickel chloride-oxygen, nickel chloride-air, copper chloride-hydrogen peroxide, copper chloride-tert-butyl hydroperoxide, copper chloride-oxygen, copper chloride-air, cuprous chloride-hydrogen peroxide, cuprous chloride-tert-butyl hydroperoxide, cuprous chloride-oxygen, cuprous chloride-air, cuprous chloride-pyridine-hydrogen peroxide, cuprous chloride-pyridine-tert-butyl hydroperoxide, ferric chloride-hydrogen peroxide, ferric chloride-oxygen, ferric trichloride-air, ruthenium trichloride-oxygen, ruthenium trichloride-air, nickel chloride, Cuprous chloride-pyridine-oxygen, cuprous chloride-pyridine-air, tetraisopropyl titanate-hydrogen peroxide, tetraisopropyl titanate-tert-butyl hydroperoxide, tetraisopropyl titanate-oxygen, tetraisopropyl titanate-air, triisopropyl vanadate-hydrogen peroxide, triisopropyl vanadate-tert-butyl hydroperoxide, triisopropyl vanadate-oxygen, triisopropyl vanadate-air.

According to the invention, the process for the preparation of the optically pure cyclic amino alcohol of formula (1) also comprises the preparation of compound (14) comprising:

reacting the compound (15) with solid phosgene and hydroxylamine hydrochloride to obtain a compound (14).

In the above production method, the reaction is preferably carried out under basic conditions, and the base used in the reaction is preferably an organic base, for example, at least one of triethylamine, N-diisopropylethylamine, N-dimethylaniline, pyridine, 2, 6-lutidine, 2-methylpyridine, 3-methylpyridine, and 4-methylpyridine.

In the preparation method, the molar ratio of the compound (15) to the alkali to the solid phosgene to the hydroxylamine hydrochloride is 1: 1-10: 0.3-1: 1-5, preferably 1: 3-6: 0.4-0.6: 1-1.5.

In the above preparation method, the reaction temperature is-20 ℃ to 150 ℃, preferably-10 ℃ to 50 ℃, for example, 0 ℃ to 5 ℃.

In the above preparation method, the solvent for the reaction may be any one of toluene, o-xylene, m-xylene, p-xylene tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, propionitrile, methyl tert-butyl ether, isopropyl ether, dioxane, ethylene glycol dimethyl ether, or a combination of two or more thereof;

the present invention also provides a process for preparing an optically pure salt of a cyclic amino alcohol represented by formula (2), comprising:

reacting the compound (1) with a compound HX to obtain a compound (2); wherein the compound HX is an organic acid or an inorganic acid.

Preferably, the compound (1) is prepared by the above-mentioned method.

According to the preparation method, the reaction temperature in the salt forming step is-20-150 ℃, and preferably 0-100 ℃; for example, 0 ℃ to 5 ℃.

In the above preparation method, the solvent used in the salt formation step may be any one of toluene, o-xylene, m-xylene, p-xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, propionitrile, methyl tert-butyl ether, isopropyl ether, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, or a combination thereof;

in the above preparation method, the compound HX may be any one of formic acid, acetic acid, oxalic acid, benzoic acid, succinic acid, fumaric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, or a combination thereof.

In the preparation method, the molar ratio of the compound (1) to the compound HX in the salt forming step is 1: 1-10; preferably 1:1 to 5.

In a specific embodiment, the preparation method of the compound (1) comprises the following steps:

1) amidation: carrying out amidation reaction on D- (-) -camphorsulfonamide (15) and solid phosgene and hydroxylamine hydrochloride to prepare a compound (14); wherein the molar ratio of the camphor-internal sulfonamide (15), the alkali, the solid phosgene and the hydroxylamine hydrochloride is 1: 1-10: 0.3-1: 1-5;

2) oxidation addition: under the condition of an oxidant, carrying out asymmetric diene addition on the compound (14) and cyclopentadiene to prepare a compound (12); wherein the molar ratio of the compound (14) to the oxidant to the cyclopentadiene is 1: 1-5: 1-10;

3) hydrolysis: hydrolyzing the compound (12) to prepare a compound (13);

4) catalytic hydrogenation: carrying out catalytic hydrogenation on the compound (13) to obtain a compound (1); compared with the prior art, the invention has the following beneficial technical effects:

1) the raw materials are cheap and easy to obtain: the cyclopentadiene and the hydroxylamine salt used in the technology are cheap and easily available chemical raw materials, and the chiral induction reagent camphor-sulfonamide can be conveniently, quantitatively and circularly used; the prior art uses expensive visfate, protectants, formatting agents and peroxyacids.

2) The atom economic synthesis route is as follows: the technology only comprises five short and easy operation steps of amidation, oxidative addition, hydrolysis, hydrogenation and salification; in the prior art, the method comprises eight steps of optical resolution, palladium-carbon hydrogenation reduction, amino protection, Grignard reagent ring opening, peroxy acid oxidation, alkaline hydrolysis, acid deprotection and acid salification; an optical resolution step, theoretically with only 50% yield, is very uneconomical;

3) high-efficiency and environment-friendly: a plurality of intermediates of the technology of the invention do not need to be separated and purified, and can be directly put into the next reaction; the only two purification and separation steps are also simple recrystallization; is easy for industrialized mass production.

The chemical name of the compound is as follows:

compound (1): (1R,3S) -3-aminocyclopentanol;

compound (2): (1R,3S) -3-aminocyclopentanol organic/inorganic acid salt;

compound (3): (2R,5S,13aR) -8-hydroxy-7, 9-dioxo-N- (2,4, 6-trifluorobenzyl) -2,3,4,5,7,9,13,13 a-octahydro-2, 5-methanopyrido (1 ', 2': 4,5) pyrazino (2,1-b) (1,3) oxazepane-10-carboxamide;

mixture (4): 1- (2, 2-dimethoxyethyl) -3-methoxy-4-oxo-5-carboxy-1, 4-dihydropyridinyl-2-carboxylic acid methyl ester;

compound (5): 2,4, 6-trifluorobenzylamine;

compound (6): (+/-) -2-azabicyclo (2.2.1) hept-5-en-3-one; (1R,4S) -2-azabicyclo (2.2.1) hept-5-en-3-one;

compound (7): (1S,4R) -2-azabicyclo (2.2.1) heptan-3-one;

compound (8): (1S,4R) -3-oxo-2-azabicyclo (2.2.1) hepta-3-carboxylic acid tert-butyl ester;

compound (9): (1S,3R) - (3-acetylcyclopentyl) -carbamic acid tert-butyl ester;

compound (10): (1R,3S) -3-t-butoxycarbonylamino cyclopentanol acetate;

mixture (11): (1S,3R) - (3-hydroxycyclopentyl) -carbamic acid tert-butyl ester;

compound (12): n- ((1S,4R) -2-oxo-3-azabicyclo (2.2.1) hept-5-ene) -N' - (D- (-) -camphorsulfonamide) carbonyl;

compound (13): (1S,4R) -2-oxo-3-azabicyclo (2.2.1) hept-5-ene;

compound (14): N-hydroxylamine-N' - (D- (-) -camphorsulfonamide) carbonyl;

compound (15): d- (-) -camphorsulfonamide;

unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.