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CN117049999A - Preparation method of Nemactetvir intermediate - Google Patents

Preparation method of Nemactetvir intermediate Download PDF

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Publication number
CN117049999A
CN117049999A CN202210488011.3A CN202210488011A CN117049999A CN 117049999 A CN117049999 A CN 117049999A CN 202210488011 A CN202210488011 A CN 202210488011A CN 117049999 A CN117049999 A CN 117049999A
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Prior art keywords
butoxycarbonyl
carboxylic acid
methyl ester
acid methyl
azabicyclo
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Inventor
蒋胜前
佘志杰
刘华
林文清
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PORTON FINE CHEMICALS Ltd
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PORTON FINE CHEMICALS Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/845—Cobalt

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention discloses a preparation method of a nemaltevir intermediate, wherein (1) (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester is subjected to addition reaction with 2, 2-dichloropropane under a catalytic system to obtain a compound (1R, 2S, 5S) -N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester; (2) Deprotecting and salifying methyl (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate to obtain methyl (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate hydrochloride; the 2, 6-bis [1- (2-isopropylphenyl imino) ethyl ] pyridine is used as a ligand, and cobalt chloride is used as a metal catalyst.

Description

Preparation method of Nemactetvir intermediate
[ technical field ]
The invention relates to the field of drug synthesis, in particular to a preparation method of a Nemactetvir intermediate.
[ background Art ]
(1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester and its corresponding salt are important intermediates of boceprevir. Boceprevir marketed in 2011 was developed by the company of pionibacterium in the united states and used for the treatment of chronic hepatitis c (WO 2005/107745).
New crown oral drug Paxlovid (Science, 2021,374,1586) disclosed by the American-section company is a commercial drug of Naomatevir combined with ritonavir, (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester and its corresponding salt are important intermediates of Naomatevir.
The synthesis method of (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester and corresponding salt mainly uses caronic anhydride as a starting material, and has the advantages of long synthesis step, complex post-treatment, potential safety hazard and high industrial production cost (WO 2004/113295), (WO 2007/075790), (CN 103435532B). In recent years, researchers report new methods for olefin cyclopropanation to efficiently synthesize such intermediates. The method is firstly reported by Uyeda subject group of American university of ferry in 2018, and authors use simple N-tert-butoxycarbonyl-2, 5-dihydropyrrole and 2, 2-dichloropropane as reaction substrates to quickly and efficiently obtain an intermediate of the boceprevir under the condition of cobalt catalysis (Angew.chem.int.ed., 2018,57,13902).
The same catalytic conditions were successively reported by the company of the American-type scion, betula platyphylla Biotechnology Co., ltd., nanj, realized
Efficient synthesis of (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and its corresponding salts (WO 2021250648A 1), (CN 114057627A). Such methods also have drawbacks such as the use of expensive anhydrous cobalt bromide as a catalyst, the synthesis of the tridentate chelating ligand 2, 6-bis [1- (2-tert-butylphenyiimino) ethyl ] pyridine, the use of expensive 2-tert-butylaniline as a starting material, extremely long reaction times (5 days), and column chromatography for post-treatment purification. These disadvantages add significantly to the cost of industrial production.
[ summary of the invention ]
In order to solve the problems, the invention provides a novel catalytic system for preparing the methyl ester hydrochloride of the (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate serving as a Nemactetavir intermediate, which is simple, greatly shortens the reaction time, improves the yield, has low cost and is easy for industrial production.
A preparation method of a nemaltevir intermediate, which comprises the following steps:
(1) The (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester is subjected to addition reaction with 2, 2-dichloropropane under a catalytic system to obtain a compound (1R, 2S, 5S) -N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester;
(2) Deprotecting and salifying methyl (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate to obtain methyl (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate hydrochloride;
the catalytic system in the step (1) comprises cobalt chloride and 2, 6-bis [1- (2-isopropylphenyl imino) ethyl ] pyridine, wherein the molar ratio of (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester to cobalt chloride to 2, 6-bis [1- (2-isopropylphenyl imino) ethyl ] pyridine is 9-11: 0.5-1.5:0.5-1.5. Preferably 9 to 11: 0.8-1.5:0.8-1.5, preferably 10:1:1
Further, the reaction condition of (1) comprises adding anhydrous cobalt chloride serving as a catalyst, 2, 6-bis [1- (2-isopropylphenyl imino) ethyl ] pyridine and tetrahydrofuran into a reaction vessel, and stirring at 20-40 ℃ for 0.5-1.5 hours to form a metal complex.
Further, zinc powder and zinc bromide are added into the formed metal complex, and then (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester and 2, 2-dichloropropane are added for reaction for 15 to 30 hours at the temperature of 20 to 40 ℃.
Further, the molar ratio of zinc powder to zinc bromide to (S) -N-t-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester is 1.9-2.1:0.5-1.5:0.5-1.5.
Further, the molar ratio of the (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester to the 2, 2-dichloropropane is 1:1.5-2.5.
Further, the reaction conditions of step (2) include: the compound (1R, 2S, 5S) -N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester and dioxane solvent are cooled to 0-5 ℃ in an ice bath, then dioxane solution of hydrogen chloride is slowly added dropwise into the reaction system, and the reaction is slowly stirred for 5-7 h after the reaction is slowly warmed to room temperature, thus obtaining (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester hydrochloride.
Compared with the prior art, the invention has the beneficial effects that:
the 2, 6-bis [1- (2-isopropylphenyl imino) ethyl ] pyridine is used as a ligand, and cobalt chloride is used as a metal catalyst.
[ description of the drawings ]
FIG. 1 shows a hydrogen spectrum of methyl (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate as product in example 1-1;
FIG. 2 is a carbon spectrum of methyl (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate as product in example 1-1;
FIG. 3 shows a hydrogen spectrum of the product methyl (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate hydrochloride in example 2-1;
FIG. 4 carbon spectrum of (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester hydrochloride of example 2-1.
[ detailed description ]
The technical means adopted by the invention and the effects thereof are further described below with reference to the examples and the attached drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting thereof.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or apparatus used were conventional products commercially available through regular channels, with no manufacturer noted.
Example 1
Synthesis of methyl (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate
Into a three-necked flask, anhydrous cobalt chloride (1.0 mmol,0.1eq.,130 mg) as a catalyst, 2, 6-bis [1- (2-isopropylphenylimino) ethyl group, was added under nitrogen atmosphere]Pyridine (1.0 mmol,0.1eq.,398 mg), and tetrahydrofuran (20 mL), were stirred at 30 ℃ for 1 hour to form a metal complex. Zinc powder (20.0 mmol,2.0eq.,1.3 g), zinc bromide (10.0 mmol,1.0eq.,2.3 g), (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (10.0 mmol,1.0eq.,2.3 g) and 2, 2-dichloropropane (20.0 mmol,2.0eq.,2.2 g) were then added and reacted at 30℃for 20H. After the reaction is finished, 300-400 meshes of silica gel is used for suction filtration, 10mL of methyl tertiary ether is used for washing filter residues, and the filtrate is concentrated. Then, 20mL of methyl tertiary ether was added for dissolution, and the mixture was washed with 20mL of saturated aqueous ammonium chloride solution, and the organic phase was extracted, dried, filtered and concentrated by suction. The residue was added with 20mL of N-heptane to precipitate a solid, the residue was washed with 10mL of N-heptane by suction filtration through celite, and the filtrate was concentrated to give a pale yellow oily compound (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [ 3.1.0)]Hexane-2-carboxylic acid methyl ester (2.38 g), yield 87.3%, with 99.6% d.e. selectivity. 1 H(400MHz,CDCl 3 ) 0.96 (s, 3H), 1.01 (s, 3H), 1.35 (d, J=4.0 Hz, 2H), 1.40 (s, 9H), 3.36-3.44 (m, 1H), 3.59-3.67 (m, 1H), 3.73-3.74 (m, 3H), 4.07-4.19 (m, 1H); see fig. 1.
13 C(100MHz,CDCl 3 ):12.7，19.5，26.4，26.8，27.5，28.4，28.5，31.2，32.1，46.5，52.3，59.5，59.9，80.1，153.3，153.9, 173.0, 173.2. See fig. 2.
Examples 1 to 2
To a three-necked flask, anhydrous cobalt chloride (1.5 mmol,0.1eq.,196 mg), 2, 6-bis [1- (2-isopropylphenylimino) ethyl ] pyridine (1.5 mmol,0.1eq.,597 mg), and tetrahydrofuran (30 mL) were added under nitrogen and stirred at 40 ℃ for 1 hour to form a metal complex. Zinc powder (20.0 mmol,2.0eq.,1.3 g), zinc bromide (10.0 mmol,1.0eq.,2.3 g), (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (10.0 mmol,1.0eq.,2.3 g) and 2, 2-dichloropropane (20.0 mmol,2.0eq.,2.2 g) were then added and reacted at 30℃for 15H. After the reaction is finished, 300-400 meshes of silica gel is used for suction filtration, 10mL of methyl tertiary ether is used for washing filter residues, and the filtrate is concentrated. Then, 20mL of methyl tertiary ether was added for dissolution, and the mixture was washed with 20mL of saturated aqueous ammonium chloride solution, and the organic phase was extracted, dried, filtered and concentrated by suction. To the residue was added 20mL of N-heptane, the solid was precipitated, the residue was suction-filtered through celite, and the filter residue was washed with 10mL of N-heptane, and the filtrate was concentrated to give methyl (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate (2.43 g) as a pale yellow oily compound in 89.1% yield with 99.6% d.e. selectivity.
Examples 1 to 3
To a three-necked flask was added anhydrous cobalt chloride (0.8 mmol,0.1eq.,104 mg), 2, 6-bis [1- (2-isopropylphenylimino) ethyl ] pyridine (0.8 mmol,0.1eq.,318 mg), and tetrahydrofuran (20 mL) under nitrogen, followed by stirring at 30℃for 1 hour to form a metal complex. Zinc powder (20.0 mmol,2.0eq.,1.3 g), zinc bromide (10.0 mmol,1.0eq.,2.3 g), (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (10.0 mmol,1.0eq.,2.3 g) and 2, 2-dichloropropane (20.0 mmol,2.0eq.,2.2 g) were then added and reacted at 30℃for 24H. After the reaction is finished, 300-400 meshes of silica gel is used for suction filtration, 10mL of methyl tertiary ether is used for washing filter residues, and the filtrate is concentrated. Then, 20mL of methyl tertiary ether was added for dissolution, and the mixture was washed with 20mL of saturated aqueous ammonium chloride solution, and the organic phase was extracted, dried, filtered and concentrated by suction. To the residue was added 20mL of N-heptane, the solid was precipitated, the residue was suction-filtered through celite, and the filter residue was washed with 10mL of N-heptane, and the filtrate was concentrated to give methyl (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate (2.35 g) as a pale yellow oily compound in 86.3% yield with 99.6% d.e. selectivity.
Example 2
Synthesis of methyl (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate hydrochloride
Into a three-necked flask, 1.39g of the compound (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid methyl ester, 10mL dioxane solvent, ice bath was cooled to 0-5 ℃. Then, 6.9mL of dioxane solution (4M) of hydrogen chloride was slowly added dropwise to the reaction system, the reaction mixture was slowly warmed to room temperature and stirred for 6 hours, and the reaction mixture was concentrated to obtain pale yellow solid powder. 5.46g of isopropanol was added to the solid and stirred at 40℃for 30 minutes, the solution being substantially clear. Then, 10.29g of methyl tertiary ether is slowly added dropwise to separate out white solid, and the mixture is stirred for 30min at the temperature of 40 ℃ after the dripping is finished. And (3) closing heating, naturally cooling to room temperature, cooling to 0-5 ℃ by using an ice bath, and stirring for 2h. Filtering, mixing isopropanol 0.75g and methyl tertiary ether 2.66g, and leaching the filter cake to obtain off-white solid (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [ 3.1.0)]1.26g of hexane-2-carboxylic acid methyl ester hydrochloride, and the yield is 90.6%. 1 H(400MHz,DMSO-d 6 ) 1.04 (s, 3H), 1.07 (s, 3H), 1.74-1.78 (m, 1H), 1.87-1.90 (m, 1H), 3.03-3.07 (m, 1H), 3.57-3.61 (m, 1H), 3.80 (s, 3H), 4.15 (d, J=4.0 Hz, 1H), 9.85 (brs, 1H); see fig. 3.
13 C(100MHz,DMSO-d 6 ):13.8, 22.2, 25.7, 29.3, 32.8, 45.6, 53.3, 53.4, 59.2, 168.8. See fig. 4.
The applicant states that the detailed method of the present invention is illustrated by the above examples, but the present invention is not limited to the detailed method described above, i.e. it does not mean that the present invention must be practiced in dependence upon the detailed method described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.

Claims (6)

1. A preparation method of a Nemactetvir intermediate is characterized by comprising the following steps of: the method comprises the following steps:
(1) The (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester is subjected to addition reaction with 2, 2-dichloropropane under a catalytic system to obtain a compound (1R, 2S, 5S) -N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester;
(2) Deprotecting and salifying methyl (1R, 2S, 5S) -N-t-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate to obtain methyl (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate hydrochloride;
the catalytic system in the step (1) comprises cobalt chloride and 2, 6-bis [1- (2-isopropylphenyl imino) ethyl ] pyridine, wherein the molar ratio of (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester to cobalt chloride to 2, 6-bis [1- (2-isopropylphenyl imino) ethyl ] pyridine is 9-11:0.5-1.5:0.5-1.5.
2. The method for preparing the Nemactetvir intermediate according to claim 1, wherein the method comprises the following steps: the reaction condition of the step (1) comprises adding anhydrous cobalt chloride serving as a catalyst, 2, 6-bis [1- (2-isopropylphenyl imino) ethyl ] pyridine and tetrahydrofuran into a reaction vessel, and stirring at 20-40 ℃ for 0.5-1.5 hours to form a metal complex.
3. The method for preparing the Nemactetvir intermediate according to claim 2, wherein the method is characterized in that: zinc powder and zinc bromide are added into the formed metal complex, and then (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester and 2, 2-dichloropropane are added for reaction for 15-30 hours at the temperature of 20-40 ℃.
4. A process for the preparation of a nemaltevir intermediate as claimed in claim 3, wherein: the molar ratio of zinc powder to zinc bromide to (S) -N-t-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester is 1.9-2.1:0.5-1.5:0.5-1.5.
5. The method for preparing the Nemactetvir intermediate according to claim 4, wherein the method comprises the following steps: the molar ratio of the (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester to the 2, 2-dichloropropane is 1:1.5-2.5.
6. The method for preparing the Nemactetvir intermediate according to claim 5, wherein the method comprises the following steps: the reaction conditions of step (2) include: the compound (1R, 2S, 5S) -N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester and dioxane solvent are cooled to 0-5 ℃ in an ice bath, then dioxane solution of hydrogen chloride is slowly added dropwise into the reaction system, and the reaction is slowly stirred for 5-7 h after the reaction is slowly warmed to room temperature, thus obtaining (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester hydrochloride.
CN202210488011.3A 2022-05-06 2022-05-06 Preparation method of Nemactetvir intermediate Pending CN117049999A (en)

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