Sacubitril intermediate, preparation method and application thereof

Abstract

The present invention belongs to the field of medicine and relates to pharmaceutical intermediates, specifically to a sacubitril intermediate, a preparation method thereof, and its application. The process route has cheap raw materials, simple operation, low production cost, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to pharmaceutical intermediates, in particular to a sacubitril intermediate, a preparation method thereof and an application thereof. Background Art

[0002] Endogenous mammalian atrial natriuretic peptide (ANP), also known as atrial natriuretic peptide (ANF), has diuretic, natriuretic, and vasodilatory functions. Natural ANF peptide is inactivated by metabolism, particularly by a degrading enzyme thought to be equivalent to NEP, which also causes metabolic inactivation of enkephalins.

[0003] Sacubitril (AHU-377) is one of the main ingredients in LCZ696 (CAS: 936623-90-4), a heart failure drug developed by Novartis. This anti-heart failure drug is a supramolecular complex formed by non-covalent bonding of valsartan and sacubitril (AHU-377). It has the dual effects of angiotensin receptor blocking and neutral endopeptidase inhibition, reducing the risk of cardiovascular disease. It is primarily used to treat heart failure, but can also be used for hypertension.

[0004] Sacubitril (AHU-377) is usually prepared through the key intermediate N-Boc amino alcohol [Formula (10-a)], the chemical name of which is: tert-butyl N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate (CAS: 1426129-50-1); its structural formula is:

[0005]

[0006] There are numerous patents in the prior art regarding the synthesis of N-Boc amino alcohols, an intermediate of sacubitril. For example, J. Med. Chem. 1995, 38, 1689-1700 reports a method for preparing sacubitril using D-tyrosine as a raw material. The synthetic route is as follows:

[0007]

[0008] The D-tyrosine used in this method is an unnatural amino acid and is expensive. The reaction process also uses an expensive trifluoromethanesulfonic anhydride reagent, which is very active and highly corrosive, and has high requirements for production equipment and operation, making it unfavorable for industrial application.

[0009] Patent WO2014032627 and patent CN105026361 disclose methods for preparing N-Boc amino alcohols. The synthetic routes are as follows:

[0010]

[0011] The main problems with this method are: the use of triphenylphosphine generates a large amount of triphenylphosphine oxide compounds after the reaction, making separation and purification difficult and resulting in a large amount of solid waste; the use of azodicarbonate compounds, which are sensitive to light, heat and vibration, and the heating process is potentially dangerous. These problems will lead to an increase in the overall production cost.

[0012] Similarly, patent CN105985225 discloses a method for preparing a sacubitril intermediate, as follows:

[0013]

[0014] This method is similar to the methods disclosed in patents WO2014 / 032627 and CN105026361, with the main difference being the use of a hydroxyl protecting agent instead of epichlorohydrin. The reaction process is essentially similar, and the same reagents are used for the same reaction type. However, the final step, because the hydroxyl group is protected with a benzyl group, requires an additional palladium-catalyzed hydrogenolysis to remove the protecting group. Although the patent reports that the yield of the preparation of N-Boc amino alcohols is improved, considering the reagent costs, the final step of removing the benzyl group by noble metal catalysis will significantly increase the cost.

[0015] Patents WO2013 / 026773 and CN103764624 disclose a method for preparing amino alcohols as intermediates of sacubitril using p-phenylbenzaldehyde as a raw material. The synthetic route is as follows:

[0016]

[0017] This process includes a catalytic hydrogenation step, but its disadvantage is that it uses precious metals Rh and Pd in large quantities, resulting in high production costs.

[0018] In addition to the chemical synthesis methods listed above, N-Boc amino alcohol intermediates can also be prepared by enzymatic methods. For example, patent CN105884656 discloses a method for preparing the intermediate by enzyme-catalyzed asymmetric reductive amination, as follows:

[0019]

[0020] In this method, benzylmagnesium bromide is used as a raw material to react with monomethyl oxalyl chloride to form ketoester; then, under the action of a brominating agent, the 4-position of the benzene ring is brominated; copper catalysis is used to couple with phenylboronic acid to obtain biphenyl ketoester; in the presence of glucose and NADP, +In the reductase CGKR2 and GDH system, the ketoester is catalyzed by asymmetric reductive amination to obtain chiral amino acid methyl ester; after Boc protection of the amino group, the carboxylic acid methyl ester is reduced to alcohol under the action of sodium borohydride and Lewis acid to obtain the key intermediate N-Boc amino alcohol.

[0021] This method has the problem of a long synthetic route. Secondly, the acyl chloride and bromination reagents are inconvenient to use. The copper-catalyzed coupling and asymmetric reductive amination steps require the use of a large amount of metallic copper and reductase. In addition, the patent does not specify the enantiomeric excess of the product after reductive amination.

[0022] In summary, the preparation of N-Boc amino alcohol (10-a), a key chiral intermediate of sacubitril, in existing reported preparation processes is limited by factors such as the availability of raw materials, reaction reagents, and post-processing processes. Furthermore, the long synthetic route, low diastereoisomer ratio, and environmental unfriendliness all contribute to high production costs and complex operations, making industrialization unsuitable. Therefore, developing a simpler, more economical, and industrially amenable production route for this key chiral intermediate, N-Boc amino alcohol (10-a), is of great significance.

[0023] Compared with the currently reported routes, the route of this application has the advantages of high yield, simple operation, continuous operation, and convenient process scale-up production. The raw materials used are cheap and easily available, and the cost is low.

[0024] Compared with the currently reported routes, the route of this application has high yield, simple operation, can realize continuous operation, and is convenient for process scale-up production. The raw materials used are cheap and easy to obtain, and the cost is low. Specifically,

[0025] 1. The auxiliary materials used in the process of this application, such as sodium hydroxide, hydrochloric acid, methanesulfonyl chloride, etc., are commonly used materials for large-scale industrial production. They are cheap and easy to obtain, and are extremely economical and have low production costs.

[0026] 2. In the process route of the present application, multiple intermediates can be continuously fed and produced without separation and purification, which can effectively reduce the energy consumption and labor costs of industrial production. For example, after the solvent is recovered under reduced pressure in Example 1, Example 2 can be directly carried out. The organic phase separated in Step 2 of Example 1 can be directly subjected to the salt formation operation and the obtained product enters the aqueous phase and is directly subjected to Example 3. Step 6 of Example 7 contains three steps of reaction and uses toluene as solvent to achieve a one-pot operation, and the purification of the product (10-a) can be completed at the same time. Summary of the Invention

[0027] The present invention relates to a process for preparing a sacubitril intermediate. By implementing the method disclosed in the present invention, the key intermediate N-Boc amino alcohol [Formula (10) and Formula (10-a)] can be efficiently prepared. The intermediate can be used for neutral endopeptidase (NEP) inhibitors or prodrugs thereof, in particular, NEP inhibitors containing a skeleton of γ-amino-δ-biphenyl-α-methylalkanoic acid or ester, such as sacubitril. The process route has cheap raw materials, simple operation, no special requirements for equipment, low production cost, is suitable for industrial production, and has great application potential and commercial value. The present invention also provides an intermediate for preparing compound (10-a).

[0028] Specifically, in one aspect, the present invention provides a process for preparing compound (10), comprising the following steps:

[0029]

[0030] Step a: Compound (6) reacts with compound (M) in the presence of a catalyst to obtain compound (7), wherein:

[0031] “*” indicates that compound (6) and compound (7) are both in R configuration or S configuration; preferably, “*” indicates that compound (6) and compound (7) are both in R configuration;

[0032] R 1 is F, Cl, Br, I or -OR 3 , R 3 Indicates C 1-6 Alkyl or C 1-6 heteroalkyl;

[0033] R 2 for wherein X is Cl, Br or I;

[0034] Pg1 is an amino protecting group;

[0035] Compound (10) has the structure: Wherein, “*” indicates that compound (10) is in R configuration or S configuration, preferably, “*” indicates that compound (10) is in R configuration.

[0036] In some embodiments, in the process of the present invention, in step a,

[0037] The catalyst is a cuprous salt, preferably CuI, CuBr, CuCl or CuCN; the amino protecting group is benzyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, methyloxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl; or

[0038] The reaction is carried out under dry and oxygen-free conditions, preferably, the reaction is carried out under dry and oxygen-free conditions with nitrogen protection; or

[0039] The reaction temperature of the reaction is -60°C to 0°C, preferably -45°C to 0°C, more preferably -30°C to -10°C, and most preferably -20°C to -15°C; or

[0040] The reaction time of the reaction is 0.5h to 3h; preferably, the reaction time is 0.8h to 2h; more preferably, the reaction time is 1h to 1.5h; and most preferably, the reaction time is 1h.

[0041] In some embodiments, in the process of the present invention, in step a, the reaction solvent of the reaction is a first solvent, and the first solvent is an organic aprotic solvent; preferably, the organic aprotic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, cyclopentane methyl ether, dichloromethane, methyl tert-butyl ether or diethyl ether, or any combination thereof.

[0042] In some embodiments, in the process of the present invention, in step a, the reaction molar equivalent ratio of compound (6) to compound (M) is 1:0.7-2, preferably 1:1-2, more preferably 1:1-1.5, and most preferably 1:1.

[0043] In some embodiments, the process of the present invention further comprises the following steps:

[0044]

[0045] Wherein, “*” indicates that compound (7), compound (8) and compound (9) are all in R configuration or S configuration, preferably, “*” indicates that compound (7), compound (8) and compound (9) are all in R configuration;

[0046] Step b: Compound (7) reacts in a second solvent under the first heating condition to obtain compound (8);

[0047] Preferably, the reaction time is 0.3h to 2h, more preferably, the reaction time is 0.3h to 1h, and most preferably, the reaction time is 0.5h;

[0048] Step c: Compound (8) is subjected to a hydrolysis reaction with a base in a third solvent under a second heating condition to obtain compound (9); wherein,

[0049] Preferably, the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate or sodium methoxide or any combination thereof;

[0050] Preferably, the molar equivalent ratio of the compound (8) to the base is 1:(0.9-5), more preferably, the molar equivalent ratio of the compound (8) to the base is 1:(1-4), further preferably, the molar equivalent ratio of the compound (8) to the base is 1:(2-4), and most preferably, the molar equivalent ratio of the compound (8) to the base is 1:3.75;

[0051] Preferably, the reaction time is 1 h to 5 h, more preferably, the reaction time is 2 h to 4 h, and most preferably, the reaction time is 3 h.

[0052] In some embodiments, in the process of the present invention, in step b and step c, the heating temperature under the first heating condition and the second heating condition are each independently 80°C to 150°C, preferably 100°C to 150°C, further preferably 110°C to 130°C, and most preferably 120°C; preferably, the heating temperature under the first heating condition and the second heating condition are the same temperature; or,

[0053] The second solvent and the third solvent are each independently n-butanol, benzene, toluene, ethylene glycol dimethyl ether, N,N-dimethylformamide, NN-dimethylacetamide; preferably, the second solvent and the third solvent are the same solvent.

[0054] In some embodiments, in the process of the present invention, after the reaction of step b is completed, a base is directly added without post-treatment to carry out the reaction of step c.

[0055] In some embodiments, the process of the present invention further comprises the following steps:

[0056]

[0057] Wherein, “*” indicates that compound (9) and compound (10) are both in R configuration or S configuration, preferably, “*” indicates that compound (9) and compound (10) are both in R configuration;

[0058] Step d: Compound (9) is subjected to amino protection reaction to obtain compound (10).

[0059] In some embodiments, in the process of the present invention, in step a, the compound (6) is prepared by the following steps:

[0060]

[0061] Wherein, the “*” on compound (2), compound (3), compound (4a), compound (4) and compound (5) indicates that compound (2), compound (3), compound (4a), compound (4) and compound (5) are all in S configuration, and the “*” on compound (6) indicates that compound (6) is in R configuration; or, the “*” on compound (2), compound (3), compound (4a), compound (4) and compound (5) indicates that compound (2), compound (3), compound (4a), compound (4) and compound (5) are all in R configuration, and the “*” on compound (6) indicates that compound (6) is in S configuration;

[0062] Pg2 is a hydroxyl protecting group, preferably a methylsulfonyl group, a trifluoromethylsulfonyl group, a p-toluenesulfonyl group or a nitrosulfonyl group; R 1 and Pg1 has the definition described in the present invention;

[0063] Step a': Compound (2) and a hydroxyl protecting agent are reacted to obtain compound (3) through a hydroxyl protecting reaction; preferably, the molar equivalent ratio of compound (2) to the hydroxyl protecting agent is 1:(1-3), more preferably, the molar equivalent ratio of compound (2) to the hydroxyl protecting agent is 1:(1-2), further preferably, the molar equivalent ratio of compound (2) to the hydroxyl protecting agent is 1:(1.2-1.5), and most preferably, the molar equivalent ratio of compound (2) to the hydroxyl protecting agent is 1:1.3;

[0064] Step b': Compound (3) reacts with an acid HY to obtain compound (4a); preferably, the acid HY is hydrochloric acid, hydrobromic acid, formic acid, hydroiodic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid;

[0065] Step c': Compound (4a) is reacted with a base to obtain compound (4); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate or potassium carbonate;

[0066] Step d': Compound (4) is reacted with an amino protecting agent to obtain compound (5); preferably, the molar equivalent ratio of compound (4) to the amino protecting agent is 1:1 to 1.5;

[0067] Step e': Compound (5) reacts in a fourth solvent under the action of an alkaline reagent to obtain compound (6); preferably, the alkaline reagent is sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate or sodium ethoxide; preferably, the molar equivalent ratio of compound (5) to the alkaline reagent is 1:(1-3), more preferably 1:(1.5-2.5), most preferably 1:2.2; preferably, the fourth solvent is tetrahydrofuran or N,N-dimethylformamide; preferably, the reaction temperature is -10°C to 50°C, further preferably, the reaction temperature is -10°C to 15°C, further preferably, the reaction temperature is -5°C to 10°C, and most preferably, the reaction temperature is 0°C to 10°C.

[0068] In some embodiments, in the process of the present invention, in step a, the compound (6) is prepared by the following steps:

[0069]

[0070] Wherein, the “*” on compound (4-1-a) and compound (5-1) indicates that compound (4-1-a) and compound (5-1) are both in S configuration, and the “*” on compound (6) indicates that compound (6) is in R configuration; or, the “*” on compound (4-1-a) and compound (5-1) indicates that compound (4-1-a) and compound (5-1) are both in R configuration, and the “*” on compound (6) indicates that compound (6) is in S configuration;

[0071] Step a": Compound (4-1-a) undergoes an amino protection reaction with an amino protecting agent in the presence of a base to obtain compound (5-1); preferably, the molar equivalent ratio of compound (4-1-a) to the amino protecting agent is 1:(0.7-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;

[0072] Step b": Compound (5-1) is reacted with triphenylphosphine and ethyl azodicarboxylate under nitrogen protection at low temperature to obtain compound (6), wherein the low temperature is -40°C to 0°C, preferably -30°C to -10°C, and more preferably -20°C to -10°C.

[0073] In some embodiments, in the process of the present invention, in step a, the compound (6) is prepared by the following steps:

[0074]

[0075] The “*” on compound (4a) indicates that compound (4a) is in S configuration, and the “*” on compound (5-2) and compound (6) indicates that compound (5-2) and compound (6) are both in R configuration; or, the “*” on compound (4a) indicates that compound (4a) is in R configuration, and the “*” on compound (5-2) and compound (6) indicates that compound (5-2) and compound (6) are both in S configuration;

[0076] Step a'': Compound (4a) reacts with a base to obtain compound (5-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; preferably, the molar equivalent ratio of compound (4a) to the base is 1:(1-3), more preferably 1:(1.2-2.5), and most preferably 1:1.5; preferably, the reaction temperature is 10°C to 100°C, more preferably, the reaction temperature is 30°C to 80°C, further preferably, the reaction temperature is 40°C to 60°C, and most preferably, the reaction temperature is 50°C;

[0077] Step b'': Compound (5-2) is further subjected to an amino protection reaction with an amino protection reagent to obtain compound (6); preferably, the molar equivalent ratio of the compound (5-2) to the amino protection reagent is 1:(0.7-2); preferably, the reaction is a low-temperature reaction, the low temperature is -5°C to 15°C, and more preferably the low temperature is 0°C to 10°C.

[0078] In another aspect, the present invention provides a compound having the following structure:

[0079]

[0080] Among them, R 1a is F, Cl, Br, I or -OR 3 , R 3 Indicates C 1-6 Alkyl or heteroatom-substituted C 1-6 alkyl;

[0081] Pg 1a is an amino protecting group, preferably benzyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, tert-methoxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl;

[0082] And when R 1a When Pg is Br or I, 1a It is not tert-butyloxycarbonyl.

[0083] In some embodiments, the compound (7a) or compound (7b) of the present invention has one of the following structures:

[0084]

[0085] In another aspect, the present invention provides a compound having the following structure:

[0086]

[0087] wherein X is F, Cl, Br or I;

[0088] Pg1 is an amino protecting group, preferably benzyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, tert-methoxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl.

[0089] In some embodiments, the compound (6a) or compound (6b) of the present invention has one of the following structures:

[0090]

[0091] In another aspect, the present invention provides a compound having the following structure:

[0092]

[0093] In another aspect, the present invention provides use of the process or compound of the present invention in the preparation of sacubitril.

[0094] Detailed description of the present invention

[0095] Definition of terms

[0096] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0097] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0098] The description methods used in the present invention, "each...is independently" and "...are each independently" and "...are independently" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0099] In the present invention, "C q1-q2 " represents the number of carbon atoms in the group being described, for example, C 1-6 The alkyl group means an alkyl group having 1 to 6 carbon atoms.

[0100] The term "alkyl" refers to a saturated, straight-chain or branched, monovalent hydrocarbon group containing from 1 to 20 carbon atoms. In another embodiment, the alkyl group contains from 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains from 1 to 4 carbon atoms; and in yet another embodiment, the alkyl group contains from 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl, n-pentyl, 2-pentyl, and the like.

[0101] The term "heteroalkyl" refers to an alkyl group in which one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, S, N, or Si. In one embodiment, the heteroalkyl group contains 1 to 6 carbon atoms; in another embodiment, the heteroalkyl group contains 1 to 4 carbon atoms; and in yet another embodiment, the heteroalkyl group contains 1 to 3 carbon atoms. Examples of heteroalkyl groups include, but are not limited to, -CH2OCH3, -CH2OCH2CH3, -CH2SCH3, -CH2SiH2CH3, -CH2NHCH3, and the like.

[0102] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

[0103] The term "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Examples of amino protecting groups include, but are not limited to, benzyloxycarbonyl (-Cbz), tert-butyloxycarbonyl (-Boc), methoxycarbonyl (-COOMe or -CO2Me), ethoxycarbonyl (-COOEt or -CO2Et), isobutyloxycarbonyl (-CO i Bu or -CO2 i Bu), isopropyloxycarbonyl (-COO i Pr or -CO2 i Pr), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc).

[0104] The term "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group. Examples of hydroxy protecting groups include, but are not limited to, methanesulfonyl (Ms), trifluoromethanesulfonyl (-Tf), p-toluenesulfonyl (-Ts), or nitrosulfonyl (-Ns).

[0105] The term "first" or "second" or "third" does not indicate the order of precedence, but is only used to distinguish the modifiers following the first or second or third. For example, the first solvent, the second solvent or the third solvent respectively represent the solvents used in the corresponding reaction; similarly, the first heating condition and the second heating condition also respectively represent the heating conditions in the corresponding reaction.

[0106] Detailed description of the invention.

[0107] By implementing the method disclosed in the present invention, the key intermediate N-Boc amino alcohol [Formula (10) or Formula (10-a)] can be efficiently prepared. The intermediate can be used to prepare neutral endopeptidase (NEP) inhibitors or prodrugs thereof, in particular, NEP inhibitors containing a backbone of γ-amino-δ-biphenyl-α-methylalkanoic acid or ester, such as sacubitril. The present invention also provides an intermediate for preparing compound (10) or compound (10-a).

[0108] Specifically, in one aspect, the present invention provides a process for preparing compound (10), comprising the following steps:

[0109]

[0110] Among them, R 1 、R 2 , Pg1 and compound (10) each have the meanings as described in the present invention;

[0111] Step a: Compound (6) reacts with compound (M) in the presence of a catalyst to obtain compound (7), wherein:

[0112] “*” indicates that both compound (6) and compound (7) are in R configuration or S configuration.

[0113] In some preferred embodiments, in step a, "*" indicates that both compound (6) and compound (7) are in R configuration, and step a is represented as follows:

[0114]

[0115] Step [a]: Compound (6a') reacts with compound (M) in the presence of a catalyst to obtain compound (7a'), wherein R 1 、R 2 and Pg1 each have the definition as described in the present invention.

[0116] In some embodiments, R 1 is F, Cl, Br, I or -OR 3 , R 3 Indicates C 1-6 Alkyl or C 1-6 heteroalkyl;

[0117] In some embodiments, R 2 for wherein X is Cl, Br or I.

[0118] In some embodiments, Pg1 is an amino protecting group.

[0119] In some embodiments, compound (10) is of the structure: Wherein, “*” indicates that compound (10) is in R configuration or S configuration.

[0120] In some preferred embodiments, compound (10) is of the structure: Wherein, “*” indicates that compound (10) is in R configuration, i.e., compound (10) is compound (10-a):

[0121] In some embodiments, in the process of the present invention, in step a, the catalyst is a cuprous salt, preferably CuI, CuBr, CuCl or CuCN.

[0122] In some embodiments, in the process of the present invention, in step a, the amino protecting group is benzyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-methoxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl.

[0123] In some embodiments, in the process of the present invention, in step a, the reaction is carried out under dry and anaerobic conditions; in some preferred embodiments, in the process of the present invention, in step a, the reaction is carried out under dry and anaerobic conditions with nitrogen protection.

[0124] In some embodiments, in the process of the present invention, in step a, the reaction temperature of the reaction is -60°C to 0°C; in some preferred embodiments, in the process of the present invention, in step a, the reaction temperature is -45°C to 0°C; in some more preferred embodiments, in the process of the present invention, in step a, the reaction temperature is -30°C to -10°C; in some most preferred embodiments, in the process of the present invention, in step a, the reaction temperature is -20°C to -15°C.

[0125] In some embodiments, in the process of the present invention, in step a, the reaction time of the reaction is 0.5h to 3h; in some preferred embodiments, in the process of the present invention, in step a, the reaction time is 0.8h to 2h; in some more preferred embodiments, in the process of the present invention, in step a, the reaction time is 1h to 1.5h; in some most preferred embodiments, in the process of the present invention, in step a, the reaction time is 1h.

[0126] In some embodiments, in the process of the present invention, in step a, the reaction solvent of the reaction is a first solvent, and the first solvent is an organic aprotic solvent; preferably, the organic aprotic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, cyclopentane methyl ether, dichloromethane, methyl tert-butyl ether or diethyl ether, or any combination thereof.

[0127] In some embodiments, in the process of the present invention, in step a, the reaction molar equivalent ratio of the compound (6) to the compound (M) is 1:0.7 to 2; in some preferred embodiments, in the process of the present invention, in step a, the reaction molar equivalent ratio of the compound (6) to the compound (M) is 1:1 to 2; in some more preferred embodiments, in the process of the present invention, in step a, the reaction molar equivalent ratio of the compound (6) to the compound (M) is 1:1 to 1.5; in some more preferred embodiments, in the process of the present invention, in step a, the reaction molar equivalent ratio of the compound (6) to the compound (M) is 1:1.

[0128] In some embodiments, the process of the present invention further comprises the following steps:

[0129]

[0130] Among them, R 1 、R 2 , Pg1 and compound (10) each have the meanings as described in the present invention;

[0131] “*” indicates that compound (7), compound (8) and compound (9) are all in R configuration or S configuration; preferably, “*” indicates that compound (7), compound (8) and compound (9) are all in R configuration;

[0132] Step b: Compound (7) reacts in a second solvent under the first heating condition to obtain compound (8);

[0133] Preferably, the reaction time is 0.3h to 2h, more preferably, the reaction time is 0.3h to 1h, and most preferably, the reaction time is 0.5h;

[0134] Step c: Compound (8) is subjected to a hydrolysis reaction with a base in a third solvent under a second heating condition to obtain compound (9); wherein,

[0135] Preferably, the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate or sodium methoxide or any combination thereof;

[0136] Preferably, the molar equivalent ratio of the compound (8) to the base is 1:(0.9-5), more preferably, the molar equivalent ratio of the compound (8) to the base is 1:(1-4), further preferably, the molar equivalent ratio of the compound (8) to the base is 1:(2-4), and most preferably, the molar equivalent ratio of the compound (8) to the base is 1:3.75;

[0137] Preferably, the reaction time is 1 h to 5 h, more preferably, the reaction time is 2 h to 4 h, and most preferably, the reaction time is 3 h.

[0138] In some embodiments, the heating temperature under the first heating condition and the second heating condition is independently 80°C to 150°C, preferably 100°C to 150°C, further preferably 110°C to 130°C, and most preferably in some embodiments, the process of the present invention, in step b and step c, is 120°C; preferably, the heating temperature under the first heating condition and the second heating condition is the same temperature.

[0139] In some embodiments, in the process of the present invention, in step b and step c, the second solvent and the third solvent are each independently n-butanol, benzene, toluene, ethylene glycol dimethyl ether, N,N-dimethylformamide, NN-dimethylacetamide; preferably, the second solvent and the third solvent are the same solvent.

[0140] In some embodiments, in the process of the present invention, after the reaction of step b is completed, a base is directly added without post-treatment to carry out the reaction of step c.

[0141] In some embodiments, the process of the present invention further comprises the following steps:

[0142]

[0143] Wherein, “*” indicates that compound (9) and compound (10) are both in R configuration or S configuration, preferably, “*” indicates that compound (9) and compound (10) are both in R configuration;

[0144] Step d: Compound (9) is subjected to amino protection reaction to obtain compound (10).

[0145] In some embodiments, in the process of the present invention, in step a, the compound (6) is prepared by the following steps:

[0146]

[0147] Wherein, the “*” on compound (2), compound (3), compound (4a), compound (4) and compound (5) indicates that compound (2), compound (3), compound (4a), compound (4) and compound (5) are all in S configuration, and the “*” on compound (6) indicates that compound (6) is in R configuration; or, the “*” on compound (2), compound (3), compound (4a), compound (4) and compound (5) indicates that compound (2), compound (3), compound (4a), compound (4) and compound (5) are all in R configuration, and the “*” on compound (6) indicates that compound (6) is in S configuration;

[0148] Pg2 is a hydroxyl protecting group, preferably a methylsulfonyl group, a trifluoromethylsulfonyl group, a p-toluenesulfonyl group or a nitrosulfonyl group; R 1 and Pg1 has the definition as defined in claim 1;

[0149] Step a': Compound (2) and a hydroxyl protecting agent are reacted to obtain compound (3) through a hydroxyl protecting reaction; preferably, the molar equivalent ratio of compound (2) to the hydroxyl protecting agent is 1:(1-3), more preferably, the molar equivalent ratio of compound (2) to the hydroxyl protecting agent is 1:(1-2), further preferably, the molar equivalent ratio of compound (2) to the hydroxyl protecting agent is 1:(1.2-1.5), and most preferably, the molar equivalent ratio of compound (2) to the hydroxyl protecting agent is 1:1.3;

[0150] Step b': Compound (3) reacts with an acid HY to obtain compound (4a); preferably, the acid HY is hydrochloric acid, hydrobromic acid, formic acid, hydroiodic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid;

[0151] Step c': Compound (4a) is reacted with a base to obtain compound (4); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;

[0152] Step d': Compound (4) is reacted with an amino protecting agent to obtain compound (5); preferably, the molar equivalent ratio of compound (4) to the amino protecting agent is 1:1 to 1.5;

[0153] Step e': Compound (5) reacts in a fourth solvent under the action of an alkaline reagent to obtain compound (6); preferably, the alkaline reagent is sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate or sodium ethoxide; preferably, the molar equivalent ratio of compound (5) to the alkaline reagent is 1:(1-3), more preferably 1:(1.5-2.5), most preferably 1:2.2; preferably, the fourth solvent is tetrahydrofuran or N,N-dimethylformamide; preferably, the reaction temperature is -10°C to 50°C, further preferably, the reaction temperature is -10°C to 15°C, further preferably, the reaction temperature is -5°C to 10°C, and most preferably, the reaction temperature is 0°C to 10°C.

[0154] In some embodiments, in the process of the present invention, in step a, the compound (6) is prepared by the following steps:

[0155]

[0156] Wherein, the “*” on compound (4-1-a) and compound (5-1) indicates that compound (4-1-a) and compound (5-1) are both in S configuration, and the “*” on compound (6) indicates that compound (6) is in R configuration; or, the “*” on compound (4-1-a) and compound (5-1) indicates that compound (4-1-a) and compound (5-1) are both in R configuration, and the “*” on compound (6) indicates that compound (6) is in S configuration;

[0157] Step a": Compound (4-1-a) undergoes an amino protection reaction with an amino protecting agent in the presence of a base to obtain compound (5-1); preferably, the molar equivalent ratio of compound (4-1-a) to the amino protecting agent is 1:(0.7-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;

[0158] Step b": Compound (5-1) is reacted with triphenylphosphine and ethyl azodicarboxylate under nitrogen protection at low temperature to obtain compound (6), wherein the low temperature is -40°C to 0°C, preferably -30°C to -10°C, and more preferably -20°C to -10°C.

[0159] In some embodiments, in the process of the present invention, in step a, the compound (6) is prepared by the following steps:

[0160] in,

[0161] The “*” on compound (4a) indicates that compound (4a) is in S configuration, and the “*” on compound (5-2) and compound (6) indicates that compound (5-2) and compound (6) are both in R configuration; or, the “*” on compound (4a) indicates that compound (4a) is in R configuration, and the “*” on compound (5-2) and compound (6) indicates that compound (5-2) and compound (6) are both in S configuration;

[0162] Step a'': Compound (4a) reacts with a base to obtain compound (5-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; preferably, the molar equivalent ratio of compound (4a) to the base is 1:(1-3), more preferably 1:(1.2-2.5), and most preferably 1:1.5; preferably, the reaction temperature is 10°C to 100°C, more preferably, the reaction temperature is 30°C to 80°C, further preferably, the reaction temperature is 40°C to 60°C, and most preferably, the reaction temperature is 50°C;

[0163] Step b'': Compound (5-2) is further subjected to an amino protection reaction with an amino protection reagent to obtain compound (6); preferably, the molar equivalent ratio of the compound (4-1-a) to the amino protection reagent is 1:(0.7-2); preferably, the reaction is a low-temperature reaction, the low temperature is -5°C to 15°C, and more preferably the low temperature is 0°C to 10°C.

[0164] In another aspect, the present invention provides a compound having the following structure:

[0165]

[0166] Among them, R 1a is F, Cl, Br, I or -OR 3 , R 3 Indicates C 1-6 Alkyl or heteroatom-substituted C 1-6 alkyl;

[0167] Pg 1a is an amino protecting group, preferably benzyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, tert-methoxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl;

[0168] And when R 1a When Pg is Br or I, 1a It is not tert-butyloxycarbonyl.

[0169] In some embodiments, the compound (7a) or compound (7b) of the present invention has one of the following structures:

[0170]

[0171] In another aspect, the present invention provides a compound having the following structure:

[0172]

[0173] wherein X is F, Cl, Br or I;

[0174] Pg1 is an amino protecting group, preferably benzyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, tert-methoxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl.

[0175] In some embodiments, the compound (6a) or compound (6b) of the present invention has one of the following structures:

[0176]

[0177] In another aspect, the present invention provides a compound having the following structure:

[0178]

[0179] In another aspect, the present invention provides use of the process or compound of the present invention in the preparation of sacubitril. DETAILED DESCRIPTION

[0180] Generally, the compounds of the present invention can be prepared by the methods described herein. The following reaction schemes and examples are provided to further illustrate the present invention. It will be appreciated by those skilled in the art that the examples are intended only to aid in understanding the present invention and should not be construed as specific limitations of the present invention.

[0181] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. The room temperature of the present invention is 10°C to 30°C or 15°C to 25°C. Unless otherwise specified, all reagents are conventional and commercially available. Silica gel columns were used for chromatographic analysis. Nuclear magnetic resonance spectra were obtained using CDC13 or DMSO-d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. Coupling constants, J, are expressed in Hertz (Hz).

[0182] The following abbreviations are used throughout this invention:

[0183]

[0184]

[0185] Example

[0186] Example 1: Synthesis of compound (6-a)

[0187] Step 1: Synthesis of compound (2-a)

[0188]

[0189] 50 g (0.47 mol) of benzaldehyde was added to 300 mL of ethanol and stirred at room temperature. 50 mL of 25% ammonia was added dropwise to the reaction system at 15-20°C. After the addition was complete, stirring was resumed at room temperature for 20 minutes. 52 g (0.56 mol, 1.2 eq) of (S)-epichlorohydrin was diluted with 50 mL of ethanol under nitrogen and slowly added dropwise to the reaction system. After the addition was complete, the system was stirred at room temperature at 25-30°C for 12 hours. GC monitoring of the reaction indicated the disappearance of epichlorohydrin, indicating the end of the reaction. Ethanol was recovered by vacuum distillation to obtain a yellow oily product. 100 mL of ethanol was added and distilled again to obtain 113 g of a pale yellow oily liquid as crude product (2-a).

[0190] Table 1: Screening of different process conditions in step 1 of Example 1

[0191]

[0192] Optimization of the reaction conditions revealed that, when other conditions remained consistent with those in the previous paragraph of Table 1, nitrogen protection during the dropwise addition of epichlorohydrin effectively reduced impurities and increased yield. Furthermore, the scaled-up reaction yielded similar results to the pilot test, demonstrating good reaction stability.

[0193] Step 2: Synthesis of compound (4-a)

[0194]

[0195] The crude product (2-a) from the previous step (113 g, 0.42 mol, 1.0 eq) was added to 400 mL of dichloromethane and stirred at room temperature. A small amount of white insoluble material was present. The filtrate was filtered and 63.7 g of triethylamine (0.629 mol, 1.5 eq) was added. The temperature was lowered to 0-10°C. 62.5 g of methanesulfonyl chloride (0.545 mol, 1.3 eq) diluted in 100 mL of dichloromethane was added dropwise. The internal temperature of the system rose to 12°C, and a white substance precipitated. After the addition was complete, the system was cooled to 4°C and stirred at this temperature for 1 hour. The reaction was monitored by normal phase HPLC, indicating the disappearance of the starting material. 400 mL of water was added, stirred thoroughly for 30 minutes, and extracted. The organic phase was washed twice with water (400 mL x 2). Take 120g of concentrated hydrochloric acid, dilute it with 240mL of water and add it to the organic phase. Stir it thoroughly at room temperature for 3-4h, let it stand and separate into layers. Wash the organic phase with 50mL of water and combine the aqueous phases to obtain a crude product (4-a) aqueous solution which is directly used in the next step reaction.

[0196] Table 2: Screening of different process conditions in step 2 of Example 1

[0197]

[0198] Under similar reaction conditions as in the previous paragraph of Table 2, a hydroxyl protection reaction was conducted on the same batch of (2-a). It was found that the reaction conversion rate was correlated with the amount of methylsulfonyl chloride used. The reaction conversion was complete when 1.3 eq was used.

[0199] Step 3: Synthesis of compound (5-a)

[0200]

[0201] The hydrochloride aqueous solution (0.374 mol, 1.0 eq) of (4-a) in step 2 was added to a 2L reaction flask. The internal temperature was lowered to 0-10°C, and then an aqueous sodium hydroxide solution (17 g of sodium hydroxide dissolved in 100 mL of water, 1.1 eq) was added dropwise to adjust the pH to between 8 and 9. The system gradually became white and turbid. After the addition was complete, the system was maintained at 0-10°C. 82 g (1 eq) of di-tert-butyl dicarbonate was diluted with 100 mL of dichloromethane and added dropwise to the reaction system. The system generated gas and released heat, and the internal temperature rose to 10-15°C. After the addition was complete, the reaction was kept warm for 2 hours. LC-MS monitoring indicated the disappearance of the reaction starting material, indicating the end of the reaction. The stratification was allowed to stand, and 137 g of dichloromethane was added to the aqueous phase for extraction. 139 g of the organic phase was separated. The organic phases were combined, washed with 122 g of water, and 132 g of the aqueous phase was separated. The organic phase was dried, filtered, and concentrated under reduced pressure to give a pale yellow oily liquid which turned into a white waxy solid after standing, 126 g of the crude product (5-a).

[0202] Characterization data of (5-a): 1 HNMR(600MHz,Chloroform-d)δ5.09(s,1H),4.89(s,1H),3.81-3.76(m,1H),3.70(dd,J=12.4,6 .1Hz,1H),3.55(dq,J=10.2,5.2Hz,1H),3.45(dt,J=14.2,6.2Hz,1H),3.13(s,3H),1.45(s,9H). 13 CNMR (151MHz, CDCl3) δ155.92,80.16,79.85,43.58,42.36,38.38,28.22.

[0203] Table 3: Screening of different process conditions in step 3 of Example 1

[0204]

[0205] Under the reaction conditions similar to those in the previous paragraph of Table 3, when the amount of di-tert-butyl dicarbonate used is 1 to 1.5 eq, the reaction can be completely converted.

[0206] Step 4: Synthesis of compound (6-a)

[0207]

[0208] 126g of the crude product (5-a) from step 3 was added to 500mL of tetrahydrofuran and stirred at room temperature to dissolve. The temperature was lowered to 0-10°C, and 20g (0.83mol, 2eq) of 60% sodium hydride was added to the reaction. Gas foaming was generated in the system. The reaction was returned to room temperature (25-30°C) and allowed to react for 1 hour. LC-MS monitoring of the reaction revealed the disappearance of the starting material. The tetrahydrofuran was recovered under reduced pressure, and dichloromethane was added. The reaction was extracted with water. The organic phase was dried and desolvated to obtain 85g of a light yellow oily liquid. Purification by vacuum distillation yielded 51.6g of a colorless oily liquid (6-a) with a GC purity of 92%. The total yield of the first five steps was 58.3%.

[0209] Characterization data of (6-a): 1 HNMR(600MHz,Chloroform-d)δ3.63(dd,J=10.0,4.1Hz,1H),3.46(dd,J=11.3, 5.9Hz,1H),2.78-2.70(m,1H),2.38(d,J=4.0Hz,1H),2.12(s,1H),1.46(s,9H). 13 CNMR (151MHz, CDCl3) δ160.96,81.15,44.50,37.12,30.92,27.43.

[0210] Table 4: Screening of different process conditions in step 4 of Example 1

[0211]

[0212] Under the reaction conditions similar to those in the previous paragraph of Table 4, when NaH was selected as the base and THF was selected as the solvent, the reaction yield was the highest.

[0213] Example 2: Synthesis of compound (6-a)

[0214] Step 1: Synthesis of compound (5-1-a)

[0215]

[0216] Take 113g of crude product 2-a (0.4mol, 1.0eq) prepared in step 1 of Example 1, add 200mL of dichloromethane as solvent, 86g of concentrated hydrochloric acid (1.0eq) is diluted with 100mL of water and added dropwise to the reaction. After the addition is complete, stir at room temperature at 25-30°C for 1h, stand for phase separation, wash the organic phase with 50mL of water and combine the aqueous phase. The aqueous phase is cooled to an internal temperature of 0-10°C, take 17g of sodium hydroxide and dissolve it in 50mL of water and slowly add dropwise to the reaction. After the addition is complete, take 65g of di-tert-butyl dicarbonate (0.417mol, 1eq) and dilute it with 100mL of dichloromethane and slowly add dropwise to the reaction system. The system releases heat and gas is generated. After the addition is complete, stir at room temperature for 2h. LC-MS detection shows that the raw material is completely converted. Stand for phase separation, wash the aqueous phase with 100mL of dichloromethane, combine the organic phases, dry, filter, and desolvate under reduced pressure to obtain 98g of a white solid as a crude product (5-1-a).

[0217] Step 2: Synthesis of compound (6-a)

[0218]

[0219] 98g (0.376mol, 1eq) of the crude product from step (5-1-a) above was added to 300mL of toluene and stirred at room temperature until dissolved. Under nitrogen, 108g (0.413mol, 1.1eq) of triphenylphosphine was added and the internal temperature was lowered to -10-20°C. 68.7g of diethyl azodicarboxylate (0.394mol, 1.05eq) was slowly added dropwise to the reaction system. The reaction gradually changed from colorless to yellow with the precipitation of solids. After the addition was complete, the reaction was kept warm for 2h. LC-MS monitoring revealed the disappearance of the starting material. Post-processing: 150mL of water was added to the reaction, stirred at room temperature, and allowed to stand for phase separation. The organic phase was desolvated under reduced pressure to yield 115g of a yellow oily liquid. Purification by vacuum distillation yielded 64g of a colorless oily liquid, pure product 6-a. GC purity was 93%. (2-a) was derived from Example 1. The total yield of the four steps, calculated from Example 1, was 73%.

[0220] Example 3: Synthesis of compound (6-a)

[0221]

[0222] The aqueous hydrochloride solution (0.356 mol, 1 eq) of (4-a) obtained in Step 2 of Example 1 was cooled to 5-10°C. 15 g of sodium hydroxide (0.392 mol, 1.1 eq) was diluted with 50 mL of water and slowly added dropwise to the reaction system. After the addition was complete, 200 mL of toluene was added to the system and the temperature was raised to 50°C. After the reaction was complete for 1-2 hours, LC-MS monitoring confirmed the complete conversion of the starting material. The system was cooled to 0-10°C and 71.5 g of di-tert-butyl dicarbonate (0.327 mol, 1 eq) was added dropwise to the reaction system. After the addition was complete, the reaction was returned to room temperature and allowed to react for 2-3 hours. LC-MS indicated the disappearance of the starting material and the formation of the desired product. The layers were allowed to stand for 2-3 hours. The aqueous phase was washed with 100 mL of toluene, and the organic phases were combined and desolvated under reduced pressure to yield 85 g of a yellow oil. Purification by vacuum distillation yielded 60 g of (6-a) as a colorless oil with a GC purity of 95%. The total yield, calculated from the five steps starting from Example 1, was 68%.

[0223] Example 4: Synthesis of Compound (10-a)

[0224] Step 1: Synthesis of compound (7-a)

[0225]

[0226] 51.6g of (6-a) (0.27mol, 1.0eq) obtained in Step 4 of Example 1 was dissolved in 200mL of tetrahydrofuran and set aside. 0.5g (0.003mol, 0.01eq) of cuprous iodide was added to the dry, deoxygenated reaction flask. Under nitrogen, 134mL (2.0M, 1.0eq) of biphenylmagnesium bromide was added to the reaction system. After the internal temperature dropped to -15 to -20°C, the tetrahydrofuran solution of (6-a) was added dropwise to the reaction system. The system gradually turned green. After the addition was complete, the temperature was maintained at -5 to -10°C for 1h. After GC monitoring, the reaction was quenched with 50mL of water. After recovering the tetrahydrofuran under reduced pressure, 300mL of dichloromethane and 400mL of water were added for extraction. The organic phase was separated, and the organic phase was dried and desolvated to obtain a white flocculent solid. This solid was then slurried with n-heptane to obtain 74g of pure product (7-a), with a yield of 79%.

[0227] Characterization data of (7-a): 1 HNMR(600MHz,Chloroform-d)δ7.56(dd,J=19.0,7.5Hz,4H),7.43(t,J=7.4Hz,2H),7.33(dd,J=15.2,7.4Hz,3H),4.85( d,J=6.8Hz,1H),4.17(s,1H),3.65(d,J=10.0Hz,1H),3.54(d,J=11.1Hz,1H),2.94(dt,J=21.5,8.7Hz,2H),1.44(s,9H). 13CNMR (151MHz, CDCl3) δ155.03,140.75,139.72,136.13,129.71,128.76,127.36,127.23,126.98,79.84,51.98,46.96,37.41,28.33.

[0228] Table 5: Screening of different process conditions in step 1 of Example 4

[0229]

[0230] Cuprous iodide is expensive. Studies have found that when the amount of cuprous iodide used is 0.01eq, it can still effectively catalyze the reaction. At the same time, after the initial amplification of the reaction, the reaction effect is almost the same as that of the small test.

[0231] Step 2: Synthesis of compound (10-a)

[0232]

[0233] 70 g (0.2 mol, 1 eq) of (7-a) was added to 200 mL of toluene, and the mixture was heated to 110°C and refluxed for 0.5 h. LC-MS monitoring revealed that (7-a) disappeared and (8-a) was generated.

[0234] Characterization data of (8-a): 1 HNMR (400MHz, DMSO-d6) δ7.83 (s, 1H), 7.69-7.64 (m, 2H), 7.61 (d, J = 8.2Hz, 2H), 7.46 (t, J = 7.6Hz, 2H), 7.40-7. 31(m,3H),4.30(t,J=8.2Hz,1H),4.15-4.05(m,1H),4.03(dd,J=8.2,5.4Hz,1H),2.84(qd,J=13.6,6.1Hz,2H); 13 CNMR(101MHz,DMSO)δ159.11,140.35,138.87,136.34,130.49,129.40,127.79,127.14,127.00,68.57,52.95,40.35.

[0235] 24 g (0.6 mol, 3 eq) of sodium hydroxide was added to the reaction, and the reaction was kept at 80°C for 3 h. LC-MS monitoring showed that 8-a disappeared and (9-a) was generated.

[0236] The system was cooled to 25-30°C, 100 mL of water was added, and then 44 g (0.2 mol, 1 eq) of di-tert-butyl dicarbonate was added dropwise. The system gradually became turbid and a white solid precipitated. After the addition was completed, the reaction was kept warm for 2 h. HPLC showed that (9-a) disappeared and (10-a) was generated. 200 mL of toluene was added to the system, and the temperature was raised to 60°C and stirred for 30 min. The system was kept warm and allowed to stand for stratification. After the aqueous phase was discarded, the organic phase was slowly cooled to 0°C to precipitate a white solid. The product was filtered and dried to obtain 53 g of a white solid (10-a) with a purity of 99.5%. The total yield of the three steps was 85.5%.

[0237] Example 5 Synthesis of Compound (8-a)

[0238] Step 1: Synthesis of compound (5-2-a)

[0239]

[0240] Example 1 Step 2 (4-a) hydrochloride aqueous solution (0.374mol, 1.0eq) was added to a 2L reaction flask. After cooling the internal temperature below 10°C, sodium hydroxide aqueous solution (17g sodium hydroxide was dissolved in 100mL water, 1.1eq) was added dropwise to adjust the pH value to between 8 and 9. The system gradually became white and turbid. After the addition was complete, the system was cooled to 0-10°C. 37g (1.1eq) of methyl chloroformate was diluted with 100mL of dichloromethane and added dropwise to the reaction system. The system produced gas and released heat, and the internal temperature rose to 10-15°C. After the addition was complete, the reaction was kept warm for 2h. After LC-MS monitoring, the reaction material disappeared and the reaction was completed. The stratification was allowed to stand, and 137g of dichloromethane was added to the aqueous phase for extraction. 139g of organic phase was separated. The organic phases were combined, the organic phase was washed with 122g of water, and 132g of aqueous phase was separated. The organic phase was dried, filtered, and concentrated under reduced pressure to give a pale yellow oily liquid which turned into a white waxy solid after standing, 105 g of the crude product (5-2-a).

[0241] Characterization data of (5-2-a): 1 HNMR(600MHz,Chloroform-d)δ5.79(s,1H),4.89(s,1H),3.81(d,J=11.6Hz,1H),3.73(dd ,J=11.9,6.0Hz,1H),3.68(s,3H),3.58(d,J=14.4Hz,1H),3.54-3.47(m,1H),3.14(s,3H); 13 CNMR (151MHz, CDCl3) δ157.12,79.40,52.15,43.36,42.30,38.04.

[0242] Step 2: Synthesis of compound (6-2-a)

[0243]

[0244] Take 105g (5-2-a) crude product (0.32mol, 1eq) from step 3, add 400mL tetrahydrofuran, stir at room temperature to dissolve, cool to 0-10°C, take 60% sodium hydride 19.2g (0.48mol, 1.5eq) to the reaction, the system produces gas foam, return to room temperature 25-30°C and react for 1h, LC-MS monitoring reaction, the raw material disappears. After decompression recovery of tetrahydrofuran, dichloromethane is added, water extraction reaction, the organic phase is dried and desolventized to obtain 58g of light yellow oily liquid. Purification by vacuum distillation gave 43.5g of colorless oily liquid (6-2-a), GC purity 95%, and the total yield of the first five steps calculated from Example 1 was 62.5%.

[0245] Characterization data of (6-2-a): 1 HNMR(600MHz,Chloroform-d)δ3.74(s,3H),3.65(dd,J=11.6,6.0Hz,1H),3.51(dd, J=11.6,5.7Hz,1H),2.82(dt,J=5.4,2.5Hz,1H),2.47(d,J=6.0Hz,1H),2.20(s,1H). 13 CNMR (151MHz, CDCl3) δ162.60,53.39,44.35,37.17,30.93.

[0246] Step 3: Synthesis of compound (7-2-a)

[0247]

[0248] Take 43 g of (6-2-a) (0.287 mol, 1.0 eq) obtained in step 2 and dissolve it in 200 mL of tetrahydrofuran for later use.

[0249] To a dry, deoxygenated reaction flask, add 0.5 g (0.0028 mol, 0.01 eq) of cuprous iodide. Under nitrogen, add 158 mL (2.0 M, 1.1 eq) of biphenylmagnesium bromide to the reaction system. After the internal temperature drops to -15 to -20°C, add a tetrahydrofuran solution of (6-a) dropwise to the reaction system. Maintain the temperature at -10 to -5°C for 1 h. Upon completion of the reaction, monitor the reaction by GC. Quench the reaction with 50 mL of water. After recovering the tetrahydrofuran under reduced pressure, extract the reaction with 300 mL of dichloromethane and 400 mL of water. Separate the layers, and dry the organic phase to remove the solvent, yielding a white, flocculent solid. Pulp the solid with n-heptane to obtain 70 g of pure product (7-2-a) in an 80% yield.

[0250] Characterization data of (7-2-a): 1HNMR(400MHz,Chloroform-d)δ7.60-7.51(m,4H),7.43(t,J=7.6Hz,2H),7.37-7.27(m,3H),5.03(d,J=7.4H z,1H),4.22(s,1H),3.68(s,3H),3.64(d,J=3.5Hz,1H),3.54(dd,J=11.2,3.2Hz,1H),2.96(t,J=6.4Hz,2H); 13 CNMR (101MHz, CDCl3) δ156.19,140.63,139.81,135.82,129.63,128.75,127.40,127.25,126.95,52.48,52.24,46.71,37.30.

[0251] Step 4: Synthesis of compound (8-a)

[0252]

[0253] Take 70 g of (7-2-a) in step 3 and add it to a 500 mL reaction bottle. Add 200 mL of toluene and heat to 110 ° C. Stir and reflux for 2 to 3 hours. LC-MS monitoring reaction (7-2-a) disappears and (8-a) is generated. After reducing pressure and recovering toluene, 59.5 g of light yellow solid is obtained, which can be directly used in the next step.

[0254] Example 6: Synthesis of Compound (8-a)

[0255] Step 1: Synthesis of compound (5-3-a)

[0256]

[0257] Example 1 Step 2 (4-a) hydrochloride aqueous solution (0.374 mol, 1.0 eq) was added to a 2L reaction flask. After cooling the internal temperature below 10°C, sodium hydroxide aqueous solution (17 g sodium hydroxide dissolved in 100 mL water, 1.1 eq) was added dropwise to adjust the pH to between 8 and 9. The system gradually became white and turbid. After the addition was complete, the system was cooled to 0-10°C. 43.9 g (1.1 eq) of ethyl chloroformate was diluted with 100 mL of dichloromethane and added dropwise to the reaction system. The system produced gas and released heat, and the internal temperature rose to 10-15°C. After the addition was complete, the reaction was kept warm for 2 hours. After LC-MS monitoring, the reaction was complete and the reaction material disappeared. The reaction was allowed to stand and the layers were separated. The aqueous phase was extracted with dichloromethane, and the organic phase was separated and combined. The organic phase was dried, filtered, and concentrated under reduced pressure to obtain a pale yellow oily liquid that turned into a white waxy solid 112 g as the crude product (5-3-a).

[0258] Characterization data of (5-3-a):1 HNMR(600MHz,Chloroform-d)δ5.44(s,1H),4.90(s,1H),4.13(d,J=6.7Hz,2H),3.80(d,J=12.2Hz,1H),3.72(d d,J=12.2,6.0Hz,1H),3.60(d,J=14.5Hz,1H),3.51(dt,J=13.7,6.0Hz,1H),3.13(s,3H),1.25(t,J=6.4Hz,3H); 13 CNMR (151MHz, CDCl3) δ156.76,79.63,61.21,43.47,42.50,38.28,14.39.

[0259] Step 2: Synthesis of compound (6-3-a)

[0260]

[0261] Take 112g (5-3-a) crude product (0.32mol, 1eq) from step 3, add 400mL tetrahydrofuran, stir at room temperature to dissolve, cool to 0-10°C, take 60% sodium hydride 26.18g (0.65mol, 2eq) to the reaction, the system produces gas foam, return to room temperature 25-30°C, react for 1h, LC-MS monitoring reaction, the starting material disappears. After decompression recovery of tetrahydrofuran, dichloromethane is added, water extraction reaction, the organic phase is dried and desolventized to obtain 54g of light yellow oily liquid. Purification by vacuum distillation gave 47.6g of colorless oily liquid (6-3-a), GC purity 94%, and the total yield of the first five steps calculated from Example 1 was 63%.

[0262] Step 3: Synthesis of compound (7-3-a)

[0263]

[0264] Take 47 g of (6-3-a) (0.287 mol, 1.0 eq) obtained in step 2 and dissolve it in 200 mL of tetrahydrofuran for later use.

[0265] To a dry, deoxygenated reaction flask, add 0.5 g (0.0028 mol, 0.01 eq) of cuprous iodide. Under nitrogen, add 158 mL (2.0 M, 1.1 eq) of biphenylmagnesium bromide to the reaction system. After the internal temperature drops to -15 to -20°C, add a tetrahydrofuran solution of (6-3-a) dropwise to the reaction system. Maintain the temperature at -5 to -10°C for 1 h. Upon completion of the reaction, monitor the reaction with GC. Quench the reaction with 50 mL of water. After recovering the tetrahydrofuran under reduced pressure, extract the reaction with 300 mL of dichloromethane and 400 mL of water. Separate the layers, and dry the organic phase to remove the solvent, yielding a white, flocculent solid. Pulp the mixture with n-heptane to obtain 77 g of pure product (7-3-a) in an 85% yield.

[0266] Characterization data of (7-3-a): 1 HNMR(400MHz,Chloroform-d)δ7.60-7.51(m,4H),7.42(t,J=7.6Hz,2H),7.32(dd,J=14.0,7.6Hz,3H),5.01(d,J=7.7Hz,1H),4.21(s,1H ), 4.12 (q, J = 7.1Hz, 2H), 3.65 (dd, J = 10.8, 3.8Hz, 1H), 3.53 (dt, J = 11.1, 3.6Hz, 1H), 2.95 (tt, J = 13.4, 6.4Hz, 2H), 1.24 (t, J = 7.1Hz, 3H); 13 CNMR (101MHz, CDCl3) δ155.78,140.64,139.76,135.89,129.63,128.73,127.36,127.22,126.93,61.04,52.35,46.75,28.29,14.51.

[0267] Step 4: Synthesis of compound (8-a)

[0268]

[0269] Take 70 g of (7-3-a) in step 3 and add it to a 500 mL reaction bottle. Add 200 mL of toluene and heat to 110 ° C. Stir and reflux for 2 to 3 hours. LC-MS monitoring reaction (7-3-a) disappears and (8-a) is generated. After decompression and return to toluene, 63 g of light yellow solid is obtained, which can be directly used in the next step reaction.

[0270] Example 7 Synthesis of Compound (10-a)

[0271] This embodiment is a kilogram-scale scale-up reaction, and the process room temperature is between 25 and 35°C.

[0272] Step 1: Synthesis of compound (2-a)

[0273]

[0274] 1.0 kg (9.42 mol) of benzaldehyde was added to 4 L of ethanol and stirred at room temperature. 1 L of 25% aqueous ammonia was added dropwise to the reaction system at 15-20°C. After the addition was complete, stirring was resumed at room temperature for 20 minutes. 1.05 kg (11.3 mol, 1.2 eq) of (S)-epichlorohydrin was diluted with 2 L of ethanol under nitrogen and slowly added dropwise to the reaction system. After the addition was complete, the system was stirred at room temperature at 25-30°C for 12 hours. GC monitoring of the reaction indicated the disappearance of epichlorohydrin, indicating the reaction was complete. Ethanol was recovered by vacuum distillation to obtain a yellow oily product. 1 L of ethanol was added and further distilled to yield 2.3 kg of a pale yellow oily liquid as crude product (2-a).

[0275] Step 2: Synthesis of compound (4-a)

[0276]

[0277] The crude product (2-a) (2.3 kg, 8.5 mol) from the previous step was added to 8 L of dichloromethane and stirred at room temperature. A small amount of white insoluble material was produced. The mixture was filtered, and 1.29 kg (12.75 mol, 1.5 eq) of triethylamine was added to the filtrate. The temperature was lowered to 0-10°C, and 1.27 kg (11.05 mol, 1.3 eq) of methanesulfonyl chloride was added dropwise. The internal temperature of the system rose to 12-20°C, and a white material precipitated. After the addition was complete, the reaction was returned to room temperature and stirred for 1 hour. The reaction was monitored by normal phase HPLC, indicating the disappearance of the starting material. 2 L of water was added, stirred thoroughly for 30 minutes, and extracted. The organic phase was washed twice with water (2 L x 2).

[0278] Take 1.2 kg of concentrated hydrochloric acid, dilute it with 2.4 L of water, and add it to the organic phase treated in the previous step. Stir it thoroughly at room temperature for 3 to 4 hours, let it stand to separate the layers, wash the organic phase with 500 mL of water, and then combine the aqueous phases to obtain a crude product (4-a) aqueous solution, which is directly used in the next step reaction.

[0279] Step 3: Synthesis of compound (5-a)

[0280]

[0281] The hydrochloride aqueous solution (7.63 mol) of step 2 (4-a) was added to the reactor. After cooling the internal temperature to below 10°C, a sodium hydroxide aqueous solution (460 g of sodium hydroxide was dissolved in 2 L of water) was added dropwise. The system gradually turned white and turbid. After the addition was complete, the system was cooled to 0-10°C. 1.7 kg (7.63 mol, 1 eq) of di-tert-butyl dicarbonate was added dropwise to the reaction system. The system produced gas and released heat, and the internal temperature rose to 10-15°C. After the addition was complete, the reaction was kept warm for 2 hours. After LC-MS monitoring, the reaction was complete and the starting material disappeared. The reaction was allowed to stand and separate. 2.7 kg of dichloromethane was added to the reaction mixture for extraction. The organic phase was allowed to stand and separated. The organic phase was washed with 2 kg of water, dried, filtered, and then distilled under reduced pressure to recover the solvent. A pale yellow oily liquid was obtained, which turned into a white waxy solid 2.5 kg as the crude product (5-a).

[0282] Step 4: Synthesis of compound (6-a)

[0283]

[0284] Take 2.5 kg of the crude product (5-a) (7.65 mol) and add 5 L of tetrahydrofuran, stir at room temperature and dissolve clearly for later use.

[0285] 2L of tetrahydrofuran was added to the reactor, and the temperature was lowered to 0-10°C. 460g (11.47mol, 1.5eq) of 60% sodium hydride was added to the reactor. After stirring for 30 minutes, a tetrahydrofuran solution of (5-a) was added dropwise over 2-3 hours. The reaction was heated to 50°C and allowed to react for 5 hours. LC-MS monitoring of the reaction revealed the disappearance of the starting material. The reaction was quenched with 500mL of water and the tetrahydrofuran was recovered under reduced pressure. 4L of dichloromethane and 2.5L of water were added for extraction. The organic phase was dried and desolventized to obtain 1.75kg of a light yellow oily liquid. Purification by vacuum distillation gave 1.1kg of a colorless oily liquid, 6-a, with a GC purity of 96%. The total yield of the first five steps was 60%.

[0286] Step 5: Synthesis of compound (7-a)

[0287]

[0288] 1.1 kg of pure product (6-a) obtained in step 4 was dissolved in 4.5 L of tetrahydrofuran and set aside. 11 g of cuprous iodide was added to a dry, deoxygenated reactor. Under nitrogen, 3 L (6 mol) of 2.0 M biphenyl magnesium bromide was added to the reaction system. After the internal temperature dropped to -15 to -20°C, the tetrahydrofuran solution of (6-a) was added dropwise to the reaction system. The system gradually turned gray-green over 2 hours of addition. The temperature was maintained for 1 to 2 hours. After GC monitoring, the reaction was quenched with 2 L of water. After recovering the tetrahydrofuran under reduced pressure, 5 L of dichloromethane and 6 L of water were added for extraction. The organic phase was separated and dried to remove the solvent to obtain 2.1 kg of a white flocculent solid. This solid was then slurried with n-heptane to obtain 1.6 kg of pure product (7-a), with a yield of 79%.

[0289] Step 6: Synthesis of compound (10-a)

[0290]

[0291] 1.6 kg of (7-a) was added to 8 L of toluene and heated to 100-110 ° C. After reflux reaction for 1-2 hours, LC-MS monitoring showed that (7-a) disappeared and (8-a) was generated. After cooling and adding 2 L of toluene, 740 g of sodium hydroxide was added to the reaction. After reflux reaction for 3 hours, LC-MS monitoring showed that (8-a) disappeared and (9-a) was generated. The system was cooled to 25-30 ° C. 1.1 kg of di-tert-butyl dicarbonate was added dropwise. The system gradually became turbid and a white solid precipitated. After the addition was complete, the reaction was kept warm for 2 hours. HPLC showed that (9-a) disappeared and (10-a) was generated. The system was added with 2 L of water and heated to 50-60 ° C. Stirred for 30 minutes, kept warm and allowed to stand for decomposition. The organic phase was separated and slowly cooled to 0 ° C. A white solid precipitated. Filtered and dried to obtain 1.25 kg of a white solid (10-a) with a purity of 99.3%. The total yield of the three steps was 87%.

[0292] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A compound, characterized in that Having the structure of formula (7a) or (7b): or ， Among them, R 1a For F, Cl, Br; Pg 1a is an amino protecting group, wherein the amino protecting group is benzyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl; And when R 1a When Br is present, Pg 1a It is not tert-butyloxycarbonyl.

2. The compound according to claim 1, characterized in that Has one of the following structures: 。 3. A compound characterized in that Having the following structure (6a) or (6b): or , wherein X is F, Cl, Br or I; Pg1 is benzyloxycarbonyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl or trimethylsilylethoxycarbonyl.

4. The compound according to claim 3, characterized in that Has one of the following structures: 。

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