METHOD FOR OBTAINING AN SMTP-7 DERIVATIVE AND ITS INTERMEDIATE CONNECTION

Abstract

A preparation method for an SMTP-7 derivative and an intermediate thereof. The present disclosure relates to a preparation method for δ-deuterated-L-ornithine. The method achieves a high yield, has mild reaction conditions, and is suitable for industrial production.

Description

A preparation method of SMTP-7 derivatives and intermediates thereof Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing an SMTP-7 derivative and an intermediate thereof. Background Art

[0002] SMTP-7 (TMS-007, Stachybotrys microspore triprenyl phenol-7), extracted in 2000 from a fungus (Stachybotrys microspora) found on fallen leaves on Iriomote Island in Okinawa Prefecture, is a small molecule plasminogen activator with a structure similar to vitamin E. It has a novel mechanism of action for dissolving blood clots and is believed to inhibit local inflammation at the site of thrombosis. SMTP-7 also exhibits anti-angiogenic, antioxidant, and tissue regeneration activities.

[0003] Plasminogen is a precursor to plasmin, which, upon activation, can generate plasmin. This protease hydrolyzes many proteins, including thrombin. SMTP-7 binds to plasminogen, altering its molecular conformation and making it more susceptible to activation by plasminogen activators. Therefore, SMTP-7 itself does not activate plasminogen; it simply facilitates the activation process. This unique combination of effects makes SMTP-7 a promising candidate for a best-in-class thrombolytic drug for the treatment of acute ischemic stroke (AIS), potentially extending the therapeutic window compared to existing standard thrombolytic drugs. (Although many antihypertensive, lipid-lowering, and anticoagulant drugs can prevent stroke, the only currently available therapeutic agent for ischemic stroke is recombinant tissue plasminogen activator (rt-PA, alteplase), a 526-amino acid glycoprotein.)

[0004] SMTP induces a conformational change in plasminogen, resulting in an increase in its binding to fibrin and ultimately in the activation of plasmin. SMTP also induces the autocleavage of plasmin to provide an angiogenic human angiostatin-like fragment. This activity is believed to underlie the antiangiogenic and antitumor effects of SMTP. Furthermore, the SMTP-induced increase in activated plasminogen may control local extracellular proteolysis, leading to tissue remodeling, wound healing, and tissue regeneration.

[0005] WO2022171151A provides an SMTP derivative, the structure of which is shown in formula (I).

[0006] Among them, δ-deuterated-L-ornithine is a key intermediate for preparing the compound represented by formula (I). Existing preparation methods have disadvantages such as low yield and low deuteration rate, and a new preparation method of δ-deuterated-L-ornithine is needed.

[0007] Summary of the Invention

[0008] In one aspect, the present disclosure provides a method for preparing a compound represented by formula (A-IV) or a salt thereof, comprising the steps of preparing a compound represented by formula (A-IV) from a compound represented by formula (A-VI), wherein:

[0009] R1 is an amino group or an amino group protected by an amino protecting group,

[0010] R2 is hydrogen or a carboxyl protecting group,

[0011] In another aspect, the present disclosure provides a method for preparing a compound represented by formula (A-IV) or a salt thereof, comprising the steps of preparing a compound represented by formula (A-IV) from a compound represented by formula (AV), wherein:

[0012] R1 is an amino group or an amino group protected by an amino protecting group,

[0013] R2 is hydrogen or a carboxyl protecting group,

[0014] In some embodiments, the method includes the steps of preparing a compound represented by formula (AV) from a compound represented by formula (AV-1), and preparing a compound represented by formula (A-IV) from a compound represented by formula (AV-1), wherein:

[0015] R1 is an amino group or an amino group protected by an amino protecting group,

[0016] R2 is hydrogen or a carboxyl protecting group,

[0017] R3 is selected from formyl, acetyl, methylsulfonyl, trifluoroacetyl and benzoyl,

[0018] In some embodiments, the amino protecting group disclosed herein is selected from acetyl, methoxyacetyl, trifluoroacetyl, trichloroacetyl, pivaloyl, formyl, benzoyl, phthaloyl, 9-fluorenylmethoxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl, such as tert-butyloxycarbonyl and benzyloxycarbonyl.

[0019] In some embodiments, the carboxyl protecting group of the present disclosure is selected from C1-C6 alkyl and C6-C 10 Aryl groups such as methyl, ethyl and tert-butyl.

[0020] In some embodiments, R1 is an amino group protected by an amino protecting group, and R2 is a carboxyl protecting group.

[0021] In some embodiments, the reaction solvent is independently selected from one or more of ethyl acetate, isopropyl acetate, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, ethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropyl alcohol, propanol, ethanol, and methanol, for example, one or more of isopropyl alcohol, propanol, ethanol, and methanol.

[0022] In some embodiments, the reaction temperature of each step is -20-50°C, for example -10-30°C.

[0023] Another aspect of the present disclosure provides a method for preparing a compound represented by formula (A-III) or a salt thereof, comprising the step of preparing a compound represented by formula (A-III) from a compound represented by formula (A-IV) in the presence of a deuterated reagent, wherein R1 and R2 are as defined above,

[0024] In some embodiments, the deuterated reagent is deuterated methanol or deuterated water.

[0025] In some embodiments, the reaction further comprises a base, such as an organic base or an inorganic base, such as at least one of triethylamine, trimethylamine, diisopropylethylamine, pyridine, or p-dimethylaminopyridine.

[0026] In some embodiments, the method further comprises the step of preparing the compound represented by formula (A-IV) or a salt thereof as described in the present disclosure.

[0027] Another aspect of the present disclosure provides a method for preparing a compound represented by formula (A-II) or a salt thereof, comprising the step of reducing a compound represented by formula (A-III) to prepare a compound represented by formula (A-II), wherein R1 and R2 are as defined above,

[0028] In some embodiments, the reduction reaction can be selected from iron powder reduction (iron powder coordinated with hydrochloric acid, acetic acid or ammonium chloride), zinc powder reduction (zinc powder coordinated with hydrochloric acid, acetic acid or ammonium chloride), metal catalyst catalytic hydrogenation (Raney nickel, palladium carbon, etc. as catalyst, hydrogen is introduced as a reducing agent), inorganic salt reducing agent reduction method (sodium sulfide, sodium dithionite or sodium borohydride, etc. as a reducing agent), hydrazine hydrate reduction method (hydrazine hydrate as a reducing agent), etc., for example, reduction is carried out under zinc powder / acetic acid conditions.

[0029] In some embodiments, R1 is an amino group protected by an amino protecting group, R2 is a carboxyl protecting group, and the method further comprises the step of deprotecting the compound represented by formula (A-II) to prepare a compound represented by formula (AI) or a salt thereof.

[0030] In some embodiments, the deprotection reaction is carried out in the presence of an acid, which may be hydrochloric acid or trifluoroacetic acid.

[0031] In some embodiments, the method further comprises the step of preparing a compound of formula (A-III) from the compound of formula (A-IV) described in the present disclosure in the presence of a deuterated reagent.

[0032] In some embodiments, the method further comprises the step of preparing the compound represented by formula (A-IV) or a salt thereof as described in the present disclosure.

[0033] Another aspect of the present disclosure provides a method for preparing a compound represented by formula (AI) or a salt thereof, comprising the steps of preparing a compound represented by formula (AI) from a compound represented by formula (A-II), wherein R1 is an amino group protected by an amino protecting group, R2 is a carboxyl protecting group,

[0034] In some embodiments, the method includes the steps of preparing a compound represented by formula (A-II) from a compound represented by formula (A-II-1), and preparing a compound represented by formula (A-II-1) from a compound represented by formula (A-II), wherein R4 is an amino group protected by an amino protecting group,

[0035] Another aspect of the present disclosure provides a method for preparing a compound represented by formula (AI) or a salt thereof, comprising:

[0036] Wherein, R1 is an amino group protected by an amino protecting group, and R2 is a carboxyl protecting group.

[0037] Another aspect of the present disclosure provides a method for preparing a compound represented by formula (AI) or a salt thereof, comprising:

[0038] Wherein, R1 is an amino group protected by an amino protecting group, R2 is a carboxyl protecting group, and R4 is an amino group protected by an amino protecting group.

[0039] Another aspect of the present disclosure provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising one or more steps of the steps of preparing a compound of formula (AI) or a salt thereof, preparing a compound of formula (A-II) or a salt thereof, preparing a compound of formula (A-III) or a salt thereof, and preparing a compound of formula (A-IV) or a salt thereof as described in the present disclosure.

[0040] In some embodiments, the method further comprises the step of fermenting the compound represented by formula (AI) or a salt thereof to obtain the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0041] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be prepared by referring to the method disclosed in WO2022171151A, which is cited herein in its entirety.

[0042] In some embodiments, each reaction solvent described in the present disclosure is independently selected from one or more of ethyl acetate, isopropyl acetate, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropyl alcohol, propanol, ethanol, methanol, and water.

[0043] In some embodiments, the preparation method of the present disclosure optionally further comprises a purification step, wherein the purification step comprises one or more of column chromatography, solvent slurrying, and recrystallization.

[0044] The salts of the compounds described in the present disclosure may be inorganic acid salts and organic acid salts. The inorganic acid salts may be hydrochlorides, sulfates, phosphates, hydrobromides, trifluoroacetates, etc., and the organic acids may be formates, acetates, sulfonates, optionally substituted alkyl sulfonates, succinates, maleates, tartrates, citrates, lactates, oxalates, gluconates, fumarates, malonates, malates, etc.

[0045] Another aspect of the present disclosure provides a compound represented by formula (AV-1) or a salt thereof, wherein:

[0046] in,

[0047] R1 is an amino group or an amino group protected by an amino protecting group,

[0048] R2 is hydrogen or a carboxyl protecting group,

[0049] R3 is selected from formyl, acetyl, methylsulfonyl, trifluoroacetyl and benzoyl,

[0050] Another aspect of the present disclosure provides a compound represented by formula (A-III), wherein R1 is an amino group or an amino group protected by an amino protecting group, R2 is hydrogen or a carboxyl protecting group,

[0051] Another aspect of the present disclosure provides a compound represented by formula (A-II) or a salt thereof, wherein R1 is an amino group or an amino group protected by an amino protecting group, R2 is hydrogen or a carboxyl protecting group,

[0052] Another aspect of the present disclosure provides a compound represented by formula (A-II-1) or a salt thereof, wherein R1 is an amino group or an amino group protected by an amino protecting group, R2 is hydrogen or a carboxyl protecting group, and R4 is an amino group protected by an amino protecting group.

[0053] The preparation method of δ-deuterated-L-ornithine disclosed in the present invention belongs to a chiral synthesis method, has high reaction yield, high product deuteration rate, mild reaction conditions, lower route cost, and is more suitable for industrial production.

[0054] In the preparation method disclosed in the present invention, the reactions connected by “→” refer to a one-step reaction to obtain the product.

[0055] "Carboxyl protecting group" is a suitable group for protecting carboxyl group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the carboxyl protecting group, as an example, preferably, the carboxyl protecting group can be a substituted or unsubstituted C 1-10 Straight or branched alkyl, substituted or unsubstituted C 2-10 Straight-chain or branched alkenyl or alkynyl, substituted or unsubstituted C 3-8 Cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 Alkyl or aryl) 3 silyl; preferably C 1-6 A straight or branched chain alkyl group, more preferably C 1-4 A straight chain or branched chain alkyl group, for example, methyl, ethyl, allyl, isopentenyl, trimethylsilylethyl, etc.

[0056] A "hydroxyl protecting group" is a group known in the art and can be used to protect a hydroxyl group. For example, see the literature ("Protective Groups in Organic Synthesis", 5th Ed. TW Greene & P.GMWuts) for hydroxyl protecting groups. As examples, including but not limited to examples, preferably, the hydroxyl protecting group can be a (C1-10 alkyl or aryl)3silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; it can be a C1-10 alkyl or substituted alkyl group, such as: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; it can be a (C1-10 alkyl or aromatic)acyl group, such as: formyl, acetyl, benzoyl, etc.; it can be a (C1-6 alkyl or C6-10 aryl)sulfonyl group; it can also be a (C1-6 alkoxy or C6-10 aryloxy)carbonyl group, which can be acetyl (Ac), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether (MTM).

[0057] An "amino protecting group" is a group known in the art that can be used to protect an amino group, as described in the literature (Protective Groups in Organic Synthesis, 5th Ed. TW Greene & P.GMWuts). Examples include, but are not limited to, carbamate protecting groups such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)-ethoxy-carbonyl (Bpoc), tert-butyloxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl, and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimido and dithiasuccinyl.

[0058] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0059] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, i.e. if there are configurational isomers in the chemical structure, the bond Can be or include both Two configurations.

[0060] Although all of the above formulae are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers. DETAILED DESCRIPTION

[0061] The present disclosure will be explained in detail below with reference to specific examples so that those skilled in the art can have a more comprehensive understanding of the present disclosure. The specific examples are only used to illustrate the technical solutions of the present disclosure and do not limit the present disclosure in any way.

[0062] Example 1 Synthesis of δ-deuterated L-ornithine

[0063] Step 1: Synthesis of Compound A2

[0064] Compound A1 (20 g, 69.2 mmol, 1.0 eq) and CDI (14.81 g, 91.35 mmol, 1.32 eq) were dissolved in THF (200 ml). CH3NO2 (21.1 g, 346 mmol, 5.0 eq) was added under nitrogen. The mixture was cooled to below 10°C in an ice-water bath. t-BuOK (1 M in THF, 139 ml, 138.4 mmol, 2.0 eq) was added dropwise. After completion of the dropwise addition, the mixture was warmed to room temperature and the reaction continued. After completion of the reaction, the reaction mixture was adjusted to pH = 2 with 2M HCl in an ice-water bath. 500 ml of water and 200 ml of EA were added for extraction. The aqueous phase was extracted with 20 ml of EA. The combined organic phases were washed with 100 ml each of water and saturated brine, dried over anhydrous sodium sulfate, filtered, and used directly in the next step.

[0065] MS-ESI: m / z 355.2[M+Na] +

[0066] Step 2: Synthesis of Compound A3

[0067] Add AcOH (1V, 23ml) to the organic phase from the previous step to form a mixed solution. Cool the mixture to 10°C under nitrogen in an ice-water bath and continue stirring for 10 minutes. Add NaBH4 (5.26g, 138.4mmol, 2.0eq) in batches. Continue the reaction in an ice-water bath until the starting materials are completely reacted. Slowly add 200ml of water to the reaction mixture under ice-water bath to quench the mixture. Extract the aqueous phase once with 20ml of EA. Combine the organic phases, add 400ml of saturated sodium bicarbonate solution, and stir for approximately 60 minutes. Extract the aqueous phase with 20ml of EA. Wash the combined organic phases with 100ml each of water and saturated brine, then dry over anhydrous sodium sulfate. Filter, and proceed directly to the next step.

[0068] MS-ESI: m / z 335.2[M+H] +

[0069] Step 3: Synthesis of Compound A4

[0070] The reaction mixture from the previous step was placed in an ice-water bath and stirred continuously under nitrogen for 10 minutes. AcO (21.19 g, 207.6 mmol, 3.0 eq) and DMAP (844 mg, 6.92 mmol, 0.1 eq) were added sequentially. After the additions were complete, the ice-water bath was removed and the mixture was allowed to warm to room temperature. After the reaction, the reaction mixture was split with 200 ml of water. The aqueous phase was extracted with 20 ml of EA. The combined organic phases were added with 300 ml of saturated sodium bicarbonate aqueous solution and stirred for 60 minutes. The combined organic phases were then separated. The aqueous phase was extracted with 20 ml of EA. The combined organic phases were washed with water and 100 ml of saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated to approximately 200 ml.

[0071] MS-ESI: m / z 399.2[M+Na] +

[0072] Step 4: Synthesis of Compound A5

[0073] The reaction mixture from the previous step was placed in a dry ice-ethanol bath. Under nitrogen, 250 ml of EtOH was added, the internal temperature dropped to -10°C, and NaBH4 (7.89 g, 207.6 mmol, 3.0 eq) was added in batches and the reaction was incubated. 2M hydrochloric acid was then slowly added to adjust the pH to 2. 300 ml of water and 100 ml of EA were added for separation. The aqueous phase was extracted with 50 ml of EA. The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution, then with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification was performed on a normal-phase silica gel column and the resulting product was thoroughly dried under vacuum to yield A5 (15.68 g, 70% yield over four steps) with a purity of 97%. Chiral purity: 99.85%.

[0074] MS-ESI: m / z 341.1[M+Na]+ .

[0075] HNMR (DMSO, 400M): 1.35~1.42(m,18H), 1.51~1.78(m,2H), 1.85~1.98(m,2H), 3.75~3.85(m,1H), 4.59(t,J=6.4Hz,2H), 7.20(t,J=6.4Hz,1H).

[0076] Step 5: Synthesis of Compound A6

[0077] A5 (24.0 g, 75.3 mmol) was added to a 250 mL single-necked flask, and a pre-dried Y-tube was installed. The atmosphere was replaced with argon three times, and THF (24.0 mL, 1 V) was added via syringe. Stirring was initiated, and then heavy water (27.4 mL, 1.507 mol) and TEA (10.5 mL, 75.3 mmol) were added sequentially via syringe. The atmosphere was replaced with argon three more times. The system was heated in an oil bath at 35°C until the reaction was complete. The reaction solution was cooled in an ice-water bath, and 72 mL of ultra-dry ethyl acetate was added, stirred for 5 min, and allowed to stand. The lower heavy water layer was removed with a long needle and discarded. The organic phase was concentrated under reduced pressure to a constant weight of 24.1 g. HNMR analysis revealed D% = 86.61%. MS-ESI: m / z 343.1 [M+Na] +

[0078] In the Y-shaped tube of the above-mentioned single-necked bottle apparatus, which was previously vacuum-dried, the argon atmosphere was replaced three times, heavy water (34.3 mL, 1.884 mol) was added with a syringe, stirring was started, and then pyridine (24.0 mL, 1 V) was added with a syringe, and the argon atmosphere was replaced three times again; the system was heated in an oil bath at 40°C and reacted until the reaction was complete; the reaction solution was controlled by HNMR (D% = 99.40%), cooled in an ice-water bath, 120 mL of ultra-dry ethyl acetate was added, stirred for 5 minutes, and then allowed to stand. The heavy water layer at the bottom was removed with a long needle for recycling. The organic phase was transferred to a constant pressure dropping funnel and added dropwise to 1N hydrochloric acid (455 mL) prepared in advance and cooled to below 10°C in an ice-water bath. The layers were separated and the aqueous phase was extracted once with 100 mL of ordinary ethyl acetate. The organic phases were combined and washed with 100 mL each of water and saturated brine, dried over anhydrous sodium sulfate (10 g) for 10 min, filtered, and concentrated under reduced pressure to constant weight to obtain 23.6 g of A6 (D% = 99.36%). The chiral data (ee value = 99.76%) showed an HPLC purity of 97.6%.

[0079] MS-ESI: m / z 343.1[M+Na] +

[0080] 1H NMR (400MHz, DMSO-d6) δ7.21-6.83(m,1H),3.84-3.71(m,1H),1.98-1.86(m,2H),1.72-1.53(m,2H),1.36-1.13(m,18H).

[0081] Step 6: Synthesis of Compound A7

[0082] A 500 mL three-necked flask was equipped with a nitrogen balloon, a thermometer, and a 250 mL constant pressure dropping funnel. Acetic acid (126 mL) was added and the atmosphere was replaced with nitrogen three times. Zinc powder (34.4 g, 529.6 mmol) was added in three batches. The addition was completed over 5 minutes and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 25-30°C for 5 minutes. Freshly prepared acetic acid solution of A6 (11.3 g, 35.3 mmol) (11.3 g of A6 dissolved in 100 mL of acetic acid) was then added dropwise. The reaction was stirred at room temperature until complete. The mixture was filtered, the filter cake was washed with 100 mL of acetic acid, and the filtrate was concentrated under reduced pressure. The residue was added with 100 mL each of dichloromethane, saturated sodium carbonate solution, and saturated brine. The mixture was stirred at room temperature for 20 minutes at 24-31°C, filtered, and the filter cake was rinsed with 200 mL of dichloromethane. The organic phases were combined, anhydrous sodium sulfate (10 g), filtered, and concentrated under reduced pressure to give the crude product. Silica gel column chromatography yielded 8.096 g of A7. Yield: 79%.

[0083] MS-ESI: m / z 291.1[M+H] + .

[0084] Step 7: Synthesis of Compound A

[0085] To a 250 mL three-necked flask, add 23.1 mL of water, cool in an ice-water bath to below 10°C, add concentrated hydrochloric acid (23.1 mL) dropwise, and then add A7 (8.050 g, 27.7 mmol) in portions. Replace the atmosphere with nitrogen three times, continue stirring below 10°C for 30 min, and then heat to 55°C to react. After the reaction is complete, cool to 30°C, concentrate under reduced pressure, add 62 mL of acetonitrile, stir at room temperature, filter, rinse the filter cake with 20 mL of acetonitrile, and dry under reduced pressure to obtain 5.461 g of compound A. The yield is 95%, the deuteration rate is 99.16%, and the CAD data (purity is 98.84%).

[0086] MS-ESI: m / z 135.2[M+H] + .

[0087] 1 H NMR(400MHz,D2O)δ3.96(t,J=6.0Hz,1H),1.98-1.84(m,2H),1.80-1.64(m,2H)

[0088] Example 2 Synthesis of δ-deuterated L-ornithine

[0089] δ-deuterated-L-ornithine dihydrochloride was prepared according to the method disclosed in WO2022171151A. The purity measured by CAD was 97.25%, and the deuteration rate was 97.3%, which was relatively low.

[0090] Example 3

[0091] Step 1: Synthesis of Compound A8

[0092] Compound A7 (18.13 kg, 62.4 mol) was dissolved in 150 L of dichloromethane, and di-tert-butyl dicarbonate (16.4 kg, 74.9 mol) and triethylamine (10.1 kg, 99.9 mol) were added. The mixture was stirred at room temperature and the reaction endpoint was monitored by TLC. 140 L of water was added and stirred, and the mixture was filtered and washed with 50 L of dichloromethane. The combined organic phases were washed with 100 L of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain a crude product, which was then slurried with petroleum ether to obtain 20.83 kg of compound A8 with a yield of 85.4%.

[0093] MS-ESI: m / z 389.2[M+H] + .

[0094] Step 2: Synthesis of Compound A

[0095] Compound A8 (4.5 kg, 9.94 mol) was added to a mixed solution of 22.5 L of acetonitrile, 13.5 L of water and 13.5 L of concentrated hydrochloric acid, and the temperature was raised to 55°C for reaction for 1 h. The mixture was stirred at room temperature overnight, concentrated, and slurried with acetonitrile. The mixture was filtered, washed, and dried in vacuo to obtain 2.36 kg of compound A, with a yield of 98.9% and a deuteration rate of 99.3%.

[0096] While the disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalents will be apparent to one skilled in the art and are intended to be included within the scope of this disclosure.

Claims

1. A method for producing a compound represented by formula (A-IV) or a salt thereof, comprising the step of obtaining a compound represented by formula (A-IV) from a compound represented by formula (A-VI), in which: R1 represents an amino group or an amino group protected by an amino protecting group, R2 represents hydrogen or a protecting group for the carboxyl group, 2. A method for producing a compound represented by formula (A-IV) or a salt thereof, comprising the step of obtaining a compound represented by formula (A-IV) from a compound represented by formula (AV), where: R1 represents an amino group or an amino group protected by an amino protecting group, R2 represents hydrogen or a protecting group for the carboxyl group, 3. The method of production according to claim 2, wherein said method comprises the steps of obtaining a compound represented by formula (AV-1) from a compound represented by formula (AV), and obtaining a compound represented by formula (A-IV) from a compound represented by formula (AV-1), where: R1 represents an amino group or an amino group protected by an amino protecting group, R2 represents hydrogen or a protecting group for the carboxyl group, R3 is selected from formyl, acetyl, methanesulfonyl, trifluoroacetyl and benzoyl, 4. The method of production according to any one of claims 1 to 3, wherein the protecting group for the amino group is selected from acetyl, methoxyacetyl, trifluoroacetyl, trichloroacetyl, pivaloyl, formyl, benzoyl, phthaloyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl and benzyloxycarbonyl, preferably tert-butoxycarbonyl and benzyloxycarbonyl.

5. The method of production according to any one of paragraphs 1-4, in which the protecting group for the carboxyl group is selected from C1-C6 alkyl and C6-C 10 aryl, preferably methyl, ethyl and tert-butyl.

6. The method of production according to any one of claims 1 to 5, in which is an amino group protected by a protecting group for an amino group, and R2 is a protecting group for a carboxyl group.

7. A method for producing a compound represented by formula (A-III) or a salt thereof, comprising the step of producing a compound represented by formula (A-III) from a compound represented by formula (A-IV) in the presence of a deuterated reagent, wherein R1 and R2 are defined in paragraph 1, and the deuterated reagent is preferably deuterated methanol or deuterium oxide, 8. The production method according to claim 7, wherein said step further comprises a base, preferably an organic base or an inorganic base, more preferably at least one of: triethylamine, trimethylamine, diisopropylethylamine, pyridine or 4-dimethylaminopyridine.

9. The method of production according to claim 7 or 8, wherein said method further comprises the step of obtaining a compound represented by formula (A-IV) or a salt thereof according to any one of claims 1 to 6.

10. A method for producing a compound represented by formula (A-II) or a salt thereof, comprising the step of reducing the compound represented by formula (A-III) to obtain a compound represented by formula (A-II), wherein R1 and R2 are defined in paragraph 1, 11. The production method according to claim 10, wherein R1 is an amino group protected by a protecting group for an amino group, and R2 is a protecting group for a carboxyl group, and said method further comprises a step of removing the protecting groups from the compound represented by formula (A-II) to obtain a compound represented by formula (A-I) or a salt thereof, 12. The method of production according to claim 10 or 11, wherein said method further comprises the step of obtaining a compound represented by formula (A-III) or a salt thereof in accordance with any one of claims 7 to 9.

13. A method for producing a compound represented by formula (A-I) or a salt thereof, comprising the step of obtaining a compound represented by formula (AI) from a compound represented by formula (A-II), in which R1 is an amino group protected by a protecting group for an amino group, and R2 is a protecting group for a carboxyl group, 14. The method of production according to claim 13, wherein said method comprises the steps of obtaining a compound represented by formula (A-II-1) from a compound represented by formula (A-II), and obtaining a compound represented by formula (A-II-1) from a compound represented by formula (A-II), wherein R4 is an amino group protected by a protecting group for an amino group, 15. The method of production according to paragraph 13 or 14, wherein said method further comprises the step of obtaining a compound represented by formula (A-II) or a salt thereof in accordance with paragraph 10.

16. A method for producing a compound represented by formula (A-I) or a salt thereof, comprising: where R1 is an amino group protected by an amino protecting group, and R2 is a carboxyl protecting group.

17. A method for producing a compound represented by formula (A-I) or a salt thereof, comprising: where is an amino group protected by an amino protecting group, R2 is a carboxyl protecting group, and R4 is an amino group protected by an amino protecting group.

18. A method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising one or more steps selected from a step of producing a compound represented by formula (A-I) or a salt thereof according to any one of claims 13 to 17, a step of producing a compound represented by formula (A-II) or a salt thereof according to any one of claims 10 to 12, a step of producing a compound represented by formula (A-III) or a salt thereof according to any one of claims 7 to 9, and a step of producing a compound represented by formula (A-IV) or a salt thereof according to any one of claims 1 to 6, 19. A compound represented by formula (AV-1) or a salt thereof, where: R1 is an amino group or an amino group protected by an amino protecting group, R2 represents hydrogen or a protecting group for the carboxyl group, R3 is selected from formyl, acetyl, methanesulfonyl, trifluoroacetyl and benzoyl, 20. A compound represented by the formula (A-III) or a salt thereof, wherein R1 is an amino group or an amino group protected by a protecting group for an amino group, and R2 is hydrogen or a protecting group for a carboxyl group, 21. A compound represented by the formula (A-II) or a salt thereof, wherein R1 is an amino group or an amino group protected by a protecting group for an amino group, and R2 is hydrogen or a protecting group for a carboxyl group, 22. A compound represented by the formula (A-II-1) or a salt thereof, wherein R1 is an amino group or an amino group protected by a protecting group for an amino group, R2 is hydrogen or a protecting group for a carboxyl group, and R4 is an amino group protected by a protecting group for an amino group, .

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