CN117105840A - Process for preparing chiral lactam derivatives - Google Patents

Process for preparing chiral lactam derivatives Download PDF

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Publication number
CN117105840A
CN117105840A CN202210535114.0A CN202210535114A CN117105840A CN 117105840 A CN117105840 A CN 117105840A CN 202210535114 A CN202210535114 A CN 202210535114A CN 117105840 A CN117105840 A CN 117105840A
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Prior art keywords
reaction
compound
process according
methanol
hydrogen
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范青明
蒋康
周涛
潘登光
赵国标
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Zhejiang Huahai Pharmaceutical Co Ltd
Zhejiang Huahai Jiancheng Pharmaceutical Co Ltd
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Zhejiang Huahai Pharmaceutical Co Ltd
Zhejiang Huahai Jiancheng Pharmaceutical Co Ltd
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Priority to CN202210535114.0A priority Critical patent/CN117105840A/en
Publication of CN117105840A publication Critical patent/CN117105840A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a method for preparing chiral lactam derivatives shown in a compound III, which comprises the step of carrying out hydrogenation cyclization reaction on a compound shown in a formula IV under the action of a metal catalyst and hydrogen to obtain the compound III. The invention also relates to a method for preparing the compound I or the acid salt thereof from the compound IV by adopting a telescoping process. The method provided by the invention is simple, convenient, quick, environment-friendly, high in reaction yield and less in byproducts.

Description

Process for preparing chiral lactam derivatives
Technical Field
The invention relates to a synthetic method for preparing chiral lactam derivatives.
Background
PF-07321332 is a novel coronavirus 3CL protease inhibitor that disrupts the subsequent RNA replication process of the propagation of the COVID-19 virus by blocking the activity of the novel COVID-19 virus propagating 3CL protease. The structural formula is as follows:
alpha-amino-2-oxo-3-pyrrolidinepropyrrolamide or an acid salt thereof is an important intermediate of PF-07321332, and the structural formula is shown in formula I:
the synthesis method of the alpha-amino-2-oxo-3-pyrrolidine propionyl amide hydrochloride is disclosed in WO2021250648 and US11124497, and comprises the steps of ammonolyzing a compound shown in a formula III in a 7M ammonia methanol system, concentrating under reduced pressure to remove a solvent to obtain a solid of a compound II, and deprotecting a group in an HCl/ethyl acetate or HCl/dioxane system to obtain a hydrochloride of the compound I, wherein the synthesis route is shown as follows:
the synthesis of compound III is generally prepared from compound IV, which has the structure shown below:
the method for synthesizing III by the compound IV comprises the following steps: the class 1 uses a metal catalyst Pd/C or platinum dioxide to reduce a compound IV, then the compound III is obtained by synthesizing amide through an internal ring of a molecule, the reaction is carried out in two steps, and the hydrogenation time is longer. The class 2 uses an inorganic reducing reagent sodium borohydride and cobalt chloride system to directly carry out reduction condensation to obtain the compound III.
Disclosure of Invention
In a first aspect the present invention provides a process for the preparation of compound III,
the method comprises the following steps:
(a) The compound shown in the formula IV is subjected to hydrogenation cyclization reaction under the action of a metal catalyst and hydrogen to obtain a compound III,
in the above compound III and compound IV, R is C 1 -C 4 Preferably methyl or ethyl.
Step (a) of the present invention is carried out in the absence of an acid and the reaction does not remain in the reduction stage.
In some embodiments, an organic base is also added in step (a).
The organic base in step (a) includes, but is not limited to, one or more of triethylamine, diisopropylamine, diisopropylethylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, p-dimethylaminopyridine, pyridine, N-methylmorpholine, tetramethylethylenediamine.
In some embodiments, the molar ratio of the organic base described in step (a) relative to the compound of formula IV is from 0.8 to 2.0, preferably from 0.9 to 1.2, for example 0.9, 1.0, 1.1, 1.2 or any range therebetween.
In some embodiments, in step (a), the pH of the reaction solution may be selected in the range of 7-12, e.g. pH 7, 8, 9, 10, 11, 12 or any two values therebetween, preferably pH 9-10.
In some embodiments, in step (a), the metal catalyst is palladium, platinum or raney nickel, preferably raney nickel.
In some embodiments, in step (a), the mass ratio of the metal catalyst to the compound of formula IV is from 1/10 to 1/50, preferably from 1/20 to 1/40.
In some embodiments, the hydrogenation in step (a) may be carried out at a pressure in the range of 0.1 to 4.5Mpa, for example, any two values in the range of 0.1Mpa, 0.2Mpa, 0.3Mpa,0.5Mpa,1Mpa,1.5Mpa,2Mpa,2.5Mpa,3Mpa,3.5Mpa,4Mpa,4.5Mpa, etc., preferably in the range of 0.1 to 1.5Mpa from the viewpoint of production safety.
In some embodiments, the reaction temperature of step (a) may be selected in the range of from 10 to 45 ℃, preferably at 20 to 40 ℃, for example 20 ℃,25 ℃,30 ℃,35 ℃,40 ℃.
In some embodiments, the solvent of the reaction of step (a) is selected from one or more of methanol, ethanol, or isopropanol;
in some embodiments, the raney nickel is built into a continuous reaction apparatus to perform a continuous flow reaction with the following parameters: the flow rate of hydrogen is 5-50 ml/min, the feeding flow rate of solution is 0.1-10 ml/min, and the column temperature is 10-45 ℃.
In some embodiments, the end point of the completion of the reaction described in step (a) may be monitored by means of TLC or the like. In general, the reaction time of the batch reactor may be selected in the range of 10 to 30 hours, for example, 10 hours, 15 hours, 20 hours, etc.
In a second aspect, the present invention provides a process for the preparation of compound I comprising the steps of:
(a) The compound shown in the formula IV is subjected to hydrogenation cyclization reaction under the action of a metal catalyst and hydrogen to obtain a compound III, and the compound III is preferably reacted in the presence of organic alkali;
(b) Removing the catalyst from the reaction solution of step (a), and then carrying out step i) or step ii):
i) Directly introducing ammonia gas, and concentrating after ammonolysis reaction to obtain a compound II;
II) concentrating to obtain a compound III, adding a solvent, introducing ammonia gas, and concentrating after ammonolysis reaction to obtain a compound II, wherein the solvent is one or more selected from methanol, ethanol and isopropanol;
(c) Deprotecting the compound II obtained in step (b) under acidic conditions to obtain a compound I or an acid salt thereof,
wherein the structural formulas of formula II and formula I are as follows:
wherein the reaction conditions of step (a) are as described in the first aspect of the invention.
In some embodiments, step (b) is conducted with ammonia gas and under positive pressure; the preferable pressure is 0.3-0.5 Mpa. Under the pressurized condition, the generation of impurities can be suppressed, and the reaction speed can be increased.
In some embodiments, the reaction temperature of step (b) may be selected in the range of 10-50 ℃, preferably the reaction is carried out at 20-40 ℃.
In some embodiments, the reaction time of the reaction described in step (b) may be selected in the range of 10-30 hours, preferably in the range of 10-20 hours.
In some embodiments, the reagent for the deprotection reaction of step (c) is one or more of hydrochloric acid, a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride, an isopropanol solution of hydrogen chloride, or trifluoroacetic acid.
In some embodiments, the acid salt of compound I of step (c) is its hydrochloride salt.
The deprotection reaction solvent is one or more selected from methanol, ethanol, isopropanol, dioxane and ethyl acetate.
In some embodiments, the process from the synthesis of compound IV to compound I is performed by a telescoping process, and purification operations such as recrystallization or extraction are not required after the reaction, so that the post-treatment operation is simple, and the industrial mass production is facilitated.
The method provided by the invention is simple, convenient, quick, environment-friendly, high in reaction yield and less in byproducts.
Detailed Description
The invention will be further illustrated with reference to specific examples.
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Moreover, the laboratory procedures used in the present invention are all conventional procedures widely used in the corresponding field.
The terms "having," "including," and "comprising" are to be construed as open-ended, meaning the presence of the recited elements but not preclude the presence, or addition of any other element or elements not recited.
All ranges recited herein include those endpoints that list ranges between the two values. All values recited herein, whether or not stated, include the degree of expected experimental error, technical error, and instrumental error for a given technique for measuring the value.
In the present invention,% is weight/weight (w/w) percent unless otherwise indicated.
Unless otherwise indicated, any numerical values, such as amounts or ranges of amounts of solvents described herein, are to be understood as modified in all instances by the term "about" as used herein, meaning that such values can vary within a range. When ranges are not recited (e.g., error ranges or standard deviations of the means presented in the charts or data tables), the term "about" is to be understood as meaning a larger range containing the recited values, as well as ranges encompassed by rounding to that number and to the extent that plus or minus 10% of the recited values are included, taking into account the significant figures.
The term "telescoping process" refers to the process of directly feeding the crude product without purification after treatment to the next reaction, and separating and purifying the crude product after several steps of purification-free processes to obtain a high-purity product.
In some embodiments of the invention, steps (a) - (c) are accomplished using a telescoping process.
In some embodiments of the invention, two or three of steps (a) - (c) may employ the same solvent, simplifying the procedure. For example, methanol is used as a solvent in each of the steps (a) to (c), or methanol is used as a solvent in the steps (a) and (b), and isopropanol is used as a solvent in the step (c).
The inventors found that the compound VI of the present invention can directly reduce the ring in one step under the action of a metal catalyst, particularly Raney nickel and hydrogen, to obtain the compound III. The invention is carried out in the absence of an acid and the reaction does not remain in the reduction stage.
The inventors have further found that the reaction yield of the process of the present invention is higher and the proportion of dimer as a by-product of the reaction is further reduced in the presence of an organic base. When the pH of the reaction system is controlled to any value between about 9 and 10, the proportion of the dimer impurity as a by-product of the reaction is further reduced.
The byproduct dimer has the structural formula as follows:
r is defined as above.
When the inorganic base is used instead, the racemization of the product is easy to cause, the main peak can be changed into double peaks, the purity of the main product is low, and the byproducts are increased.
1) Synthesis of Compound III:
EXAMPLE 1 Synthesis of Compound III
31.4g of Compound IV,240ml of methanol, 1g of Raney Nickel and 18g of triethylamine are added to the hydrogenation reactor, and the pH is controlled to about 11; nitrogen is replaced, hydrogen is introduced, the reaction pressure is controlled to be 3.0-4.0 MPa, the temperature is controlled to be 30-35 ℃, after 14h of hydrogenation, the TLC plate raw material basically has no residue, the reaction is finished, the catalyst is removed by filtration, and the filtered reaction liquid shows a product compound III in the peak area through HPLC detection results: dimeric impurity = 5.7:1, raw material conversion was calculated to be 99.7%.
EXAMPLE 2 Synthesis of Compound III
31.4g of Compound IV,240ml of methanol, 1g of Raney Nickel and 12g of triethylamine are added to the hydrogenation reactor, and the pH is controlled to about 10; nitrogen replacement, introducing hydrogen, controlling the reaction pressure to be 2-3.0 MPa, controlling the temperature to be 20-25 ℃, and after hydrogenation for 20 hours, basically keeping no residue of TLC (thin layer chromatography) plate raw materials, finishing the reaction, filtering to remove a catalyst, and detecting a result of the filtered reaction liquid by HPLC (high performance liquid chromatography) to show a product compound III in a peak area: dimeric impurity = 18.2:1, raw material conversion 98.2%.
EXAMPLE 3 Synthesis of Compound III
31.4g of Compound IV,240ml of ethanol, 1.2g of Raney Nickel and 12g of triethylamine are added to the hydrogenation reactor, and the pH is controlled to about 9; nitrogen is replaced, hydrogen is introduced, the reaction pressure is controlled to be 1.0-2.0 MPa, the temperature is controlled to be 25-30 ℃, after 15 hours of hydrogenation, the TLC plate raw material basically has no residue, the reaction is finished, the catalyst is removed by filtration, the solvent is evaporated to obtain 25.6g of product, and the filtered reaction liquid shows the product compound III in the peak area through HPLC detection results: dimeric impurity = 10:1, raw material conversion was calculated to be 99.8%.
EXAMPLE 4 Synthesis of Compound III
31.4g of Compound IV,240ml of methanol, 1.2g of Raney Nickel and then 14.4g of diisopropylethylamine were added to the hydrogenation vessel and the pH was controlled to about 9; nitrogen is replaced, hydrogen is introduced, the reaction pressure is controlled to be 0.6-1.0 MPa, the temperature is controlled to be 20-25 ℃, after 17 hours of hydrogenation, the TLC plate raw material basically has no residue, the reaction is finished, the catalyst is removed by filtration, and the filtered reaction liquid shows a product compound III in the peak area through HPLC detection results: dimeric impurity = 15.5:1, raw material conversion was calculated to be 99.1%.
EXAMPLE 5 Synthesis of Compound III
31.4g of compound IV,240ml of methanol, 1.2g of Raney nickel and nitrogen are added into a hydrogenation kettle for replacement, hydrogen is introduced, the reaction pressure is controlled to be 0.6-1.0 MPa, the temperature is controlled to be 25-30 ℃, after hydrogenation is carried out for 20 hours, the raw material point of a TLC (thin layer chromatography) point plate is basically disappeared, the reaction is stopped, a catalyst is filtered, a reaction liquid is sampled and detected by HPLC (high performance liquid chromatography), and the result shows that the product compound III in the peak area: dimer impurity = 3.8:1, raw material conversion was calculated to be 99.7%, dimer impurity produced more.
EXAMPLE 6 Synthesis of Compound III
The continuous flow equipment is internally provided with 1g of Raney nickel catalyst, the flow rate of hydrogen is controlled to be 40ml/min, a reaction solution containing 31.4g of compound IV,240ml of methanol and 12g of triethylamine is fed at the flow rate of 1.5ml/min, the column temperature is set to be 20-30 ℃ for reaction, the reaction solution is sampled and detected by HPLC, and the result shows that the product compound III in the peak area: dimer impurity=14.7:1, the conversion of the raw material is calculated to be 99.9%, and after the reaction, the collected feed liquid is concentrated to obtain 26.1g of product.
2) Synthesis of Compound II:
EXAMPLE 7 Synthesis of Compound II
14.3g of Compound III,100ml of methanol are introduced into a reaction flask; nitrogen is replaced, ammonia gas is introduced, the pressure is controlled to be 0.3MPa, the temperature is 30-35 ℃, after 18 hours of reaction, the TLC plate raw material basically has no residue, the reaction is finished, the temperature is controlled to be 40-50 ℃, the concentration is reduced to no fraction, 13.2g of compound II is obtained, and the conversion rate of the raw material is 100% according to the HPLC detection result.
EXAMPLE 8 Synthesis of Compound II
14.3g of Compound III,100ml of methanol are introduced into a reaction flask; nitrogen is replaced, ammonia gas is introduced, the pressure is controlled to be 0.5MPa, the temperature is 30-35 ℃, after the reaction is carried out for 12 hours, the TLC plate raw material basically has no residue, the reaction is finished, the temperature is controlled to be 40-50 ℃, the decompression concentration is carried out until no fraction is obtained, 13.4g of compound II is obtained, and the conversion rate of the raw material is 100% according to the HPLC detection result.
Comparative example 1 Synthesis of Compound II
14.3g of compound III, 55g of 7M methanolic ammonia solution, controlling the temperature to be 30-35 ℃, reacting for 48 hours, wherein the TLC plate raw material still remains, stopping the reaction, controlling the temperature to be 40-50 ℃ and concentrating under reduced pressure until no fraction is obtained to 13.4g, and indicating the raw material conversion rate to be 70.6 percent according to HPLC detection results.
3) Synthesis of compound I hydrochloride:
EXAMPLE 9 Synthesis of Compound I hydrochloride
15.7g of Compound IV,120ml of methanol, 0.5g of Raney Nickel and 6g of triethylamine are added to the hydrogenation reactor, and the pH is controlled to about 9; nitrogen is replaced, hydrogen is introduced, the reaction pressure is controlled to be 0.6-1.0 MPa, the temperature is 30-35 ℃, after 17 hours of hydrogenation, the TLC plate raw material is basically free from residue, the reaction is finished, the catalyst is removed by filtration, the filtrate is transferred into a pressure reaction bottle, ammonia is introduced, the pressure is controlled to be 0.3MPa, the temperature is 30-35 ℃, after 17 hours of reaction, the TLC plate raw material is basically free from residue, the reaction is finished, and the temperature is controlled to be 40-50 ℃ and reduced pressure concentration is carried out until no fraction exists. 50ml of ethanol is added into the concentrate, the temperature is controlled to be 20-30 ℃, and 29g of ethanol solution of hydrogen chloride is added dropwise; after the dripping is finished, controlling the temperature to be 20-30 ℃, keeping the temperature, stirring and reacting for 4 hours, basically keeping the spot-plate raw materials free of residues, finishing the reaction, filtering, adding 40ml of ethanol into a filter cake, and stirring for 2-3 hours at the temperature of 40-50 ℃; slowly cooling to room temperature, filtering, leaching with proper amount of ethanol, filtering cake, and oven drying to obtain 6.7g of compound I hydrochloride, with HPLC purity of 99.6% and total yield of 65.2%.
EXAMPLE 10 Synthesis of Compound I hydrochloride
15.7g of Compound IV,120ml of methanol, 0.5g of Raney Nickel and 6g of triethylamine are added to the hydrogenation reactor, and the pH is controlled to about 9; and (3) nitrogen replacement, introducing hydrogen, controlling the reaction pressure to be 0.6-1.0 MPa, controlling the temperature to be 30-35 ℃, after 17h of hydrogenation, basically keeping no residue of the TLC plate raw materials, after the reaction is finished, filtering to remove the catalyst, and concentrating the filtrate to be dry.
Adding 60ml of isopropanol into distilled substrate, stirring and dissolving, then introducing ammonia gas, controlling the pressure to be 0.3MPa, controlling the temperature to be 30-35 ℃, reacting for 17 hours, basically keeping no residue of TLC (thin layer chromatography) plate raw materials, and concentrating under reduced pressure at the temperature of 40-50 ℃ until no fraction exists after the reaction is finished.
50ml of isopropanol is added into the concentrate, the temperature is controlled to be 20-30 ℃, and 29g of isopropanol solution of hydrogen chloride is added dropwise; after the dripping is finished, controlling the temperature to be 20-30 ℃, keeping the temperature, stirring and reacting for 4 hours, basically keeping the spot-plate raw materials free of residues, finishing the reaction, filtering, adding 40ml of isopropanol into a filter cake, and stirring for 2-3 hours at the temperature of 40-50 ℃; slowly cooling to room temperature, filtering, leaching with proper amount of isopropanol, filtering cake, and oven drying to obtain 5.7g of compound I hydrochloride with HPLC purity of 99.3% and total yield of 57.4%.
EXAMPLE 11 Synthesis of Compound I hydrochloride
The continuous flow equipment is internally provided with 0.5g of Raney nickel catalyst, the flow rate of hydrogen is controlled to be 40ml/min, a reaction solution containing 15.7g of compound IV,120ml of methanol and 6g of triethylamine is injected at the flow rate of 0.5ml/min, the column temperature is set to be 20-30 ℃ for reaction, after the reaction, the feed liquid is collected into a pressure reaction bottle, ammonia gas is introduced, the pressure is controlled to be 0.3MPa, the temperature is controlled to be 30-35 ℃, after the reaction is carried out for 17 hours, the raw materials of a TLC (thin layer chromatography) point plate basically have no residue, the reaction is finished, and the reduced pressure concentration is controlled to be 40-50 ℃ until no fraction exists.
50ml of ethanol is added into the concentrate, the temperature is controlled to be 20-30 ℃, and 29g of ethanol solution of hydrogen chloride is added dropwise; after the dripping is finished, controlling the temperature to be 20-30 ℃, keeping the temperature, stirring and reacting for 4 hours, basically keeping the spot-plate raw materials free of residues, finishing the reaction, filtering, adding 40ml of ethanol into a filter cake, and stirring for 2-3 hours at the temperature of 40-50 ℃; slowly cooling to room temperature, filtering, leaching with proper amount of ethanol, filtering cake, and oven drying to obtain 6.5g of compound I hydrochloride with HPLC purity of 99.7% and total yield of 64.8%.
It is to be understood that the foregoing detailed description and examples are exemplary only and are not considered as limiting the scope of the invention, which is defined only by the appended claims and equivalents thereof. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those relating to the methods of the present invention, or any combination of such changes and modifications, may be made without departing from the spirit and scope of the present invention.

Claims (18)

1. A process for the preparation of compound III, wherein,
the method comprises the following steps:
(a) The compound shown in the formula IV is subjected to hydrogenation cyclization reaction under the action of a metal catalyst and hydrogen to obtain a compound III,
in the above compound III and compound IV, R is C 1 -C 4 Preferably methyl or ethyl.
2. The process of claim 1, wherein in step (a) an organic base is also added.
3. The method of claim 2, wherein the organic base is selected from one or more of triethylamine, diisopropylamine, diisopropylethylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, p-dimethylaminopyridine, pyridine, N-methylmorpholine, tetramethylethylenediamine.
4. The process according to claim 2, wherein in step (a) the molar ratio of the organic base to the compound of formula IV is from 0.8 to 2.0, preferably from 0.9 to 1.2.
5. The process according to claim 1 or 2, wherein in step (a) the pH of the reaction system is 7 to 12, preferably 9 to 10.
6. The process according to claim 1 or 2, wherein in step (a) the solvent of the reaction is one or more of methanol, ethanol, isopropanol.
7. A process according to claim 1 or 2, wherein the metal catalyst is palladium, platinum or raney nickel, preferably raney nickel.
8. The process according to claim 1 or 2, wherein in step (a) the mass ratio of the metal catalyst to the compound of formula IV is from 1/10 to 1/50, preferably from 1/20 to 1/40.
9. A process according to claim 1 or 2, wherein in step (a) the hydrogen pressure is from 0.1 to 4.5Mpa, preferably from 0.1 to 1.5Mpa.
10. The process according to claim 1 or 2, wherein in step (a) the reaction temperature of the hydrogenation cyclization reaction is 10-45 ℃, preferably 20-40 ℃.
11. The process of claim 1 or 2, the reaction further being carried out in a continuous flow apparatus, the metal catalyst being placed in the continuous reaction apparatus, wherein the parameters of the continuous flow reaction are as follows: the flow rate of hydrogen is 5-50 ml/min, the feeding flow rate of solution is 0.1-10 ml/min, and the column temperature is 10-45 ℃.
12. A process for the preparation of compound I comprising the steps of:
step (a) as claimed in any one of claims 1 to 11;
(b) Removing the catalyst from the reaction solution of step (a), and then carrying out step i) or step ii):
i) Directly introducing ammonia gas, and concentrating after ammonolysis reaction to obtain a compound II;
II) concentrating to obtain a compound III, adding a solvent, introducing ammonia gas, and concentrating after ammonolysis reaction to obtain a compound II, wherein the solvent is one or more selected from methanol, ethanol and isopropanol;
(c) Removing protecting group from the compound II under acidic condition to obtain a compound I or acid salt thereof,
the structural formulas of formulas II and I are shown below:
13. the method of claim 12, wherein the ammonolysis reaction in step (b) is performed under positive pressure conditions; the positive pressure is preferably 0.3 to 0.5Mpa.
14. The process according to claim 12, wherein the reaction temperature of step (b) is 10-50 ℃, preferably 20-40 ℃; the reaction time in step (b) is 10 to 30 hours, preferably 10 to 20 hours.
15. The method of claim 12, wherein in step (c) the reagent of the deprotection reaction is one or more of hydrochloric acid, a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride, an isopropanol solution of hydrogen chloride, or trifluoroacetic acid.
16. The method of claim 12, wherein in step (c), the solvent of the deprotection reaction is one or more of methanol, ethanol, isopropanol, dioxane, and ethyl acetate.
17. The method of claim 12, wherein in step (c), the acid salt of compound I is the hydrochloride salt.
18. The method of any one of claims 12-17, wherein steps (a) - (c) are accomplished using a telescoping process.
CN202210535114.0A 2022-05-17 2022-05-17 Process for preparing chiral lactam derivatives Pending CN117105840A (en)

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