Preparation method of milobalin key intermediate

Abstract

The invention discloses a preparation method of a milobalin key intermediate. The invention provides a preparation method of a compound 2, which comprises the following step: crystallizing a crude product of the compound 2 in acetonitrile to obtain the compound 2. In the preparation of the compound 2, the purity and the dr value of the compound 2 can be greatly improved only through one-time crystallization operation. The method has the advantages of simple and easy operation, easy impurity control, high yield and low production cost, is suitable for large-scale industrial production, and has great economic and social benefits. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for preparing a key intermediate of milgabalin. Background Art

[0002] Peripheral neuropathic pain (PNP) is a pathological pain caused by peripheral nerve injury or dysfunction due to various reasons. Clinically common PNP includes diabetic peripheral neuropathy (PDPN), postherpetic neuralgia (PHN), chronic pain after surgery, etc. PDPN is the most common complication of diabetes, with an incidence rate of over 60% in diabetic patients, and approximately 22 million patients are deeply troubled by PDPN; PHN is pain that persists for 1 month or more after the healing of herpes zoster rash, with an annual incidence rate of 3.9 - 42.0 per 100,000, and 9% - 34% of herpes zoster patients will develop PHN; the incidence rate of chronic pain after surgery varies greatly depending on the type of surgery, and it is reported to be between 10% and 50%. The incidence rates after amputation, thoracotomy, and coronary artery bypass surgery are the highest, reaching 30% - 50%.

[0003] Mirogabalin besylate is a γ - aminobutyric acid analogue developed by Daiichi Sankyo Co., Ltd. in Japan for the treatment of peripheral neuropathic pain. Its mechanism is to act on the α2δ - 1 subunit of the voltage - sensitive calcium channel complex. Its indications are post - herpetic neuralgia, diabetic neuropathy, and peripheral nervous system diseases.

[0004] In patent CN104755456B, the preparation route of milgabalin besylate (1) involves the following key intermediate 2, whose chemical name is (1R,5S,6S) - 6 - cyano - 3 - ethylbicyclo[3.2.0]hept - 3 - en - 6 - yl]acetic acid.

[0005]

[0006] In patent CN104755456B, the synthesis of key intermediate 2 starts with (1R,5S) - 3 - ethylbicyclo[3.2.0]hept - 3 - en - 6 - one (3), and undergoes a total of 4 steps including Knoevenagel condensation, addition with NaCN, decarboxylation and hydrolysis, and salt formation and dissociation. Among them, NaCN is used in the addition reaction, and the dr value of the addition product is low. After decarboxylation and hydrolysis, it is necessary to form a salt with an amine to resolve it, so that the ee value of compound 6 can reach 98%, and the total yield is only about 50%. The use of NaCN and the cumbersome operation of improving optical purity by salt formation and then dissociation are very unfavorable for the large - scale industrial production of milgabalin.

[0007] Summary of the Invention

[0008] The main object of the present invention is to provide a method for synthesizing the key intermediate 2 of milnacipran in view of the above problems and deficiencies. Starting from (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (3), through three steps of reaction including Knoevenagel condensation with dibenzyl malonate, Nagata hydrocyanation reaction (TMSCN / Et3Al), decarboxylation hydrolysis and crystallization, the key intermediate 2 of milnacipran is obtained. In the preparation of compound 8, the Nagata hydrocyanation reaction is used to synthesize compound 8, avoiding the use of NaCN, and the addition stereoselectivity of compound 8 is better; in the preparation of compound 2, only one crystallization operation is required to greatly improve the purity and dr value of compound 2. The operation is simple and easy, the impurities are easy to control, the yield is relatively high, the production cost is low, it is suitable for large-scale industrial production, and has great economic and social benefits.

[0009] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0010] The present invention provides a method for preparing a compound 8, which comprises the following steps: in a solvent, compound 7 reacts with a Nagata reagent as follows to obtain compound 8;

[0011]

[0012] wherein, R 1 is benzyl (Bn), phenyl (Ph), 2-methoxyethyl (-CH2CH2OCH3), 2-(2-methoxyethoxy)ethyl (-CH2CH2OCH2CH2OCH3).

[0013] The conditions of the method for preparing the compound 8 described above can be the conventional conditions for such reactions in the art.

[0014] In one embodiment, R 1 is benzyl or -CH2CH2OCH3.

[0015] In one embodiment, the two Rs 1 are the same.

[0016] In one embodiment, the solvent is an organic solvent, preferably an alkane solvent and / or an aromatic hydrocarbon solvent.

[0017] In one embodiment, the alkane solvent is n-hexane or n-heptane, preferably n-hexane.

[0018] In one embodiment, the aromatic hydrocarbon solvent is benzene, toluene or xylene.

[0019] In one embodiment, the Nagata reagent can be commercially available (R2 )2AlCN, or R 3 It is prepared by CN and alkyl aluminum reagent;

[0020] Among them, R 2 is Me, Et, i-Pr or i-Bu;

[0021] R 3 is Na, K, H or TMS;

[0022] The alkylaluminum reagent is EtAlCl2, Me3Al, Et3Al or Et2AlCl.

[0023] In one scenario, R 2 For Me or Et.

[0024] In one scenario, R 3 For TMS.

[0025] In one embodiment, the alkylaluminum reagent is Et3Al.

[0026] In one embodiment, when the Nagata reagent is composed of R 3 When CN and the alkyl aluminum reagent are prepared, the alkyl aluminum reagent and R 3 The molar ratio of CN is 1:(1-5), preferably 1:(2-4), for example 1:3.

[0027] In one embodiment, when the Nagata reagent is composed of R 3 When CN and the alkylaluminum reagent are prepared, the alkylaluminum reagent is in the form of a solution, preferably a solution dissolved in an alkane solvent (such as n-hexane); preferably, the concentration of the alkylaluminum reagent solution is 2 mol / L.

[0028] In one embodiment, when the Nagata reagent is composed of R 3 When CN and the alkyl aluminum reagent are prepared, R 3 CN is added together with the alkylaluminum reagent at one time or in batches.

[0029] In one scheme, when R 3 When CN and the alkyl aluminum reagent are added together, R 3 The molar ratio of CN to the alkylaluminum reagent may be comparable (eg, about 1:1).

[0030] In one scheme, when R 3 When CN and the alkyl aluminum reagent are added in batches, the first batch of R 3 The added molar amount of CN can be the same as that of the alkyl aluminum reagent, and the remaining R 3 CN can be added simultaneously with compound 8.

[0031] In one embodiment, the Nagata reagent can be prepared from R 3 CN and the alkylaluminum reagent at 65 - 120 °C, preferably at 65 - 75 °C; preferably, the preparation time is 0.1 - 5 hours, such as 1 hour.

[0032] In one embodiment, the molar ratio of the Nagata reagent to Compound 7 is 1:(1 - 5), preferably 1:(2 - 4), such as 1:3.

[0033] In one embodiment, when the Nagata reagent is prepared from Et3Al and TMSCN, the molar ratio of Et3Al to TMSCN is 1:(1 - 5), preferably 1:(2 - 4), such as 1:3.

[0034] In one embodiment, when the Nagata reagent is prepared from Et3Al and TMSCN, Et3Al is a solution dissolved in n - hexane. Preferably, the concentration of the Et3Al n - hexane solution is 2 mol / L.

[0035] In one embodiment, when the Nagata reagent is prepared from Et3Al and TMSCN, TMSCN can be added to Et3Al all at once or in batches; when TMSCN is added in batches, the molar amount of the first batch of TMSCN added is the same as that of Et3Al, and the remaining TMSCN is added simultaneously with Compound 8.

[0036] In one embodiment, the reaction temperature is 40 - 120 °C, preferably 55 - 75 °C, such as 55 °C, 60 °C, 65 °C, 70 °C or 75 °C.

[0037] In one embodiment, the reaction time is until no more product is formed, such as 0.5 - 10 hours, or for example 2 hours.

[0038] In one embodiment, the preparation method includes the following steps: in an organic solvent, R 3 CN reacts with the alkylaluminum reagent and then reacts with Compound 7.

[0039] In one embodiment, the preparation method includes the following steps: in an organic solvent, R 3 CN reacts with the alkylaluminum reagent at 65 - 120 °C for 0.5 - 3 hours, and then reacts with Compound 7 at 55 - 65 °C for 0.5 - 3 hours.

[0040] In one embodiment, the reaction further includes the following post-treatment steps: sodium bicarbonate solution (preferably saturated sodium bicarbonate solution) is added to the reaction solution, and then potassium sodium tartrate solution (preferably saturated potassium sodium tartrate solution) is added, followed by stirring. The aqueous layer is extracted with an organic solvent (preferably n-heptane and / or ethyl acetate), and the organic layer is extracted with sodium bicarbonate solution (such as 5% sodium bicarbonate solution). The solvent is removed from the organic layer to obtain Compound 8.

[0041] In one embodiment, the method for preparing Compound 8 further includes the following steps: in a solvent, in the presence of a catalyst and a base, Compound 3 and Compound 10 react as follows to obtain Compound 7;

[0042]

[0043] wherein, R 1 is benzyl (Bn), phenyl (Ph), 2-methoxyethyl (-CH2CH2OCH3) or 2-(2-methoxyethoxy)ethyl (-CH2CH2OCH2CH2OCH3);

[0044] The catalyst is one or more of TiCl4, TiCl3(OiPr) and AlCl3.

[0045] The conditions for the method for preparing Compound 8 can be the conventional conditions for such reactions in the art.

[0046] In one embodiment, R 1 is benzyl or -CH2CH2OCH3.

[0047] In one embodiment, the catalyst is TiCl4.

[0048] In one embodiment, the solvent is an organic solvent, preferably an ether solvent or an aromatic hydrocarbon solvent.

[0049] In one embodiment, the ether solvent is a cyclic ether solvent, preferably tetrahydrofuran.

[0050] In one embodiment, the aromatic hydrocarbon solvent is benzene, toluene or xylene.

[0051] In one embodiment, the base is an organic base, preferably a nitrogen-containing organic base, such as pyridine.

[0052] In one embodiment, the molar ratio of Compound 3 to the catalyst is 1:(0.1 - 3), preferably 1:(0.5 - 2.5), more preferably 1:(1 - 2).

[0053] In one embodiment, the molar ratio of Compound 3 to Compound 10 is 1:(1 - 1.5), preferably 1:(1 - 1.2), such as 1:1.05.

[0054] In one embodiment, the molar ratio of Compound 3 to the base is 1:(2 - 10), preferably 1:(4 - 6), such as 1:5.

[0055] In one embodiment, the temperature of the reaction is -20 to 25 °C, preferably -5 to 5 °C.

[0056] In one embodiment, the reaction time is until no more product is formed, preferably 2 to 24 hours, more preferably 2 to 12 hours, such as 2, 4, 6, 8 or 10 hours.

[0057] In one embodiment, the preparation method comprises the following steps: In the solvent, in the presence of the catalyst and the base, Compound 3 and Compound 10 react to obtain Compound 7.

[0058] In one embodiment, the preparation method comprises the following steps: In the solvent (such as tetrahydrofuran), the catalyst (such as TiCl4), Compound 3 and Compound 10 react at -5 to 5 °C, and then the base (such as pyridine) is added for reaction to obtain Compound 7.

[0059] In one embodiment, the preparation method further comprises the following post-treatment steps: quenching the reaction with water, extracting with a mixed solution of n-heptane and ethyl acetate (preferably n-heptane and ethyl acetate in a ratio of 4:1), washing with a sodium chloride solution (preferably saturated sodium chloride solution), and removing the solvent (preferably removing the solvent under reduced pressure) to obtain Compound 7.

[0060] The present invention provides a method for preparing Compound 2, which comprises the following steps:

[0061] (1) In the solvent, Compound 7 and the Nagata reagent react as follows to obtain Compound 8;

[0062]

[0063] (2) In the solvent, Compound 8 reacts in the presence of a base to obtain Compound 2,

[0064]

[0065] wherein, R 1 is benzyl (Bn), phenyl (Ph), 2-methoxyethyl (-CH2CH2OCH3) or 2-(2-methoxyethoxy)ethyl (-CH2CH2OCH2CH2OCH3);

[0066] In Step 1, the reactants and conditions of the reaction are as described in the preparation method of the above Compound 8.

[0067] The conditions for the preparation method of the compound 2 can be the conventional conditions for such reactions in the art.

[0068] In one embodiment, R 1 is benzyl or -CH2CH2OCH3.

[0069] In one embodiment, in step (2), the solvent is an alcohol solvent, a nitrile solvent, or a mixed solvent of a nitrile solvent and water, preferably an alcohol solvent.

[0070] In one embodiment, in step (2), the alcohol solvent is one or more of methanol, ethanol, and isopropanol, preferably ethanol.

[0071] In one embodiment, in step (2), the nitrile solvent is acetonitrile.

[0072] In one embodiment, in step (2), the volume ratio of the nitrile solvent to water in the mixed solvent of the nitrile solvent and water is (1-10):1, preferably 4:1.

[0073] In one embodiment, in step (2), the base is an inorganic strong base, preferably an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, more preferably potassium hydroxide.

[0074] In one embodiment, in step (2), the molar ratio of compound 8 to the base is 1:(2-10), preferably 1:(2-4), such as 1:2.

[0075] In one embodiment, in step (2), it includes the following steps: in the solvent, compound 8 reacts with an alcoholic solution of the base, and then reacts with an aqueous solution of the base to obtain compound 2;

[0076] Preferably, the alcoholic solution can be a methanol solution, an ethanol solution, and / or an isopropanol solution;

[0077] Preferably, the concentration of the alcoholic solution of the base can be 0.1-10 mol / L, such as 0.1, 0.2, 0.5, 0.7, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mol / L;

[0078] Preferably, the concentration of the aqueous solution of the base can be 0.1-10 mol / L, such as 0.1, 0.2, 0.5, 0.7, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mol / L;

[0079] Preferably, the temperature for reacting with the alcoholic solution of the base can be 80-140 °C, preferably 100-110 °C;

[0080] Preferably, the temperature of the reaction with the aqueous solution of the base can be room temperature, preferably 0 - 50 °C, more preferably 15 - 30 °C;

[0081] Preferably, the reaction time with the alcoholic solution of the base is until no more product is formed, preferably 4 - 12 hours, such as 7 hours;

[0082] Preferably, the reaction time with the aqueous solution of the base is until no more product is formed, preferably 1 - 6 hours, such as 2 hours.

[0083] In one embodiment, in step (2), it includes the following steps: In ethanol, compound 8 reacts with a 0.1 - 10 mol / L ethanolic potassium hydroxide solution at 100 - 110 °C, and then reacts with a 0.1 - 10 mol / L aqueous potassium hydroxide solution to obtain compound 2;

[0084] Preferably, in ethanol, compound 8 reacts with a 0.5 mol / L ethanolic potassium hydroxide solution at 100 - 110 °C, is filtered, washed with ethanol, and reacts with a 1 mol / L aqueous potassium hydroxide solution to obtain compound 2.

[0085] In one embodiment, in step (2), it further includes the following post - treatment steps: After removing the solvent, it is extracted with a halogenated alkane solvent, the pH of the aqueous layer is adjusted to 1 - 3, extracted with a halogenated alkane solvent again, and the organic phase is removed of the solvent to obtain the crude product of compound 2; The crude product of compound 2 is crystallized in acetonitrile at - 10 - 30 °C to obtain compound 2.

[0086] In one embodiment, in the post - treatment step, the solvent is an alcohol solvent, such as ethanol.

[0087] In one embodiment, in the post - treatment step, the halogenated alkane solvent is dichloromethane (DCM).

[0088] In one embodiment, in the post - treatment step, the pH is 2.

[0089] In one embodiment, in the post - treatment step, the temperature of the crystallization is - 10 - 30 °C, such as - 20 °C.

[0090] In one embodiment, in the post - treatment step, the crystallization time is 1 - 20 hours, such as 4, 6, 8, 10 or 12 hours.

[0091] In one embodiment, in the post - treatment step, the mass - to - volume ratio (g / mL) of the crude product of compound 2 to acetonitrile is 1:(0.2 - 10), preferably 1:(0.5 - 2), such as 1:1, 6.1:5 or 6.4:5.

[0092] The present invention also provides a method for preparing Compound 2, which comprises the following steps: in acetonitrile, crude Compound 2 is crystallized to obtain Compound 2;

[0093]

[0094] The temperature of the crystallization is -10 to -30 °C.

[0095] The conditions for the crystallization can be the conventional conditions for such crystallization in the art.

[0096] In one embodiment, the temperature of the crystallization is -10, -15, -20, -25 or -30 °C.

[0097] In one embodiment, the time for the crystallization is 1 to 20 hours, such as 2, 4, 6, 8, 10 or 12 hours.

[0098] In one embodiment, the mass-volume ratio of the crude Compound 2 to acetonitrile is 1:(0.2 to 10), preferably 1:(0.5 to 2), such as 1:1, 6.1:5 or 6.4:5; the mass-volume ratio is g:mL.

[0099] In one embodiment, the purity of the crude Compound 2 is 50 to 98%, such as 91.8%, 92.1%, 83.9%, 52.0%.

[0100] In one embodiment, the diastereoisomer Compound 2' in the crude Compound 2 has a content of 1 to 10%, preferably 2 to 8%, such as 3.5%, 3.8%, 7.4% or 7.6%.

[0101] In one embodiment, the dr value of the crude Compound 2 is 30:1 to 5:1, such as 26:1, 24:1, 11:1 or 7:1.

[0102] In one embodiment, the crude Compound 2 is prepared by the above method for preparing Compound 2.

[0103] The present invention also provides a Compound 7 or a Compound 8, and their structures are respectively shown as follows:

[0104]

[0105] Wherein, R 1 is benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

[0106] The term "Nagata reagent" is a cyanating reagent for catalyzing the Nagata cyanohydrin reaction, and can be a commercially available dialkylaluminum cyanide reagent (for example, (R 2)2AlCN), or can be prepared from a cyanide and an alkylaluminum reagent (for example, R 3 CN and an alkylaluminum reagent).

[0107] Among them, R 2 is an alkyl group, such as Me, Et, i-Pr or i-Bu;

[0108] R 3 is Na, K, H or TMS;

[0109] The above alkylaluminum reagents are EtAlCl2, Me3Al, Et3Al or Et2AlCl.

[0110] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the present invention.

[0111] The reagents and raw materials used in the present invention are all commercially available.

[0112] The positive and progressive effects of the present invention are as follows:

[0113] (1) In the preparation of compound 8, the Nagata hydrocyanation reaction is used to synthesize compound 8, avoiding the use of NaCN, and the addition stereoselectivity of compound 8 is better;

[0114] (2) In the preparation of compound 2, only one crystallization operation is required to greatly improve the purity and dr value of compound 2.

[0115] The operation of the present invention is simple and easy to implement, impurities are easy to control, the yield is relatively high, the production cost is low, it is suitable for large-scale industrial production, and has great economic and social benefits. Detailed implementation mode

[0116] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods not specified in the following examples are carried out according to conventional methods and conditions, or are selected according to the product specifications.

[0117] Example 1:

[0118]

[0119] Add anhydrous THF (1.5 L) to a 3 L jacketed flask. After cooling the temperature to 5 - -5 °C, inject titanium tetrachloride (TiCl4, 80.5 ml, 734.3 mmol, 2 eq.). Stir for 15 min at this temperature. Then add compound 3 (50 g, 367 mmol, 1 eq.) and dibenzyl malonate (96.3 ml, 385.5 mmol, 1.05 eq.) to the jacketed flask. Stir for 2 h at this temperature. Add pyridine (147.7 ml, 1.84 mol, 5 eq.) to the above reaction solution. Stir for 2 h at this temperature, and then let the reaction proceed overnight. Add 500 ml of water to quench this reaction. After liquid separation, extract the aqueous layer (500 ml × 4) with n-heptane and ethyl acetate (4:1). Wash the organic layer with saturated brine (200 ml), and concentrate under reduced pressure to obtain compound 7a as a yellow oil, 145.6 g, yield 98.5%, HPLC purity 94.8%.

[0120] LCMS[M+H] + 403[M-H] - 401。

[0121] 1 H NMR(400MHz,Chloroform-d)δ7.40–7.27(m,10H),5.26–5.15(m,5H),4.29–4.15(m,1H),3.29(ddd,J=19.0,8.5,3.6Hz,1H),2.87(q,J=6.8Hz,1H),2.75–2.56(m,2H),2.26–2.13(m,1H),2.05(q,J=7.3Hz,2H),1.01(t,J=7.4Hz,3H).

[0122] Example 2:

[0123]

[0124] At room temperature, triethylaluminum (Et3Al, 2M n-hexane solution, 500 ml, 1.0 mol, 3 eq.) and trimethylsilyl cyanide (TMSCN, 374.3 ml, 3.0 mol, 9 eq.) were added to a 5 L jacketed flask and stirred at 65 - 75 °C for 1 h. Then, at room temperature, the compound 7a (133.8 g, 333.0 mmol, 1 eq.) obtained in Example 1 was added to the above solution and stirred at 55 - 65 °C for 1 h. The temperature was lowered to 5 - -5 °C, and a saturated sodium bicarbonate solution (500 ml) was slowly added dropwise, followed by the addition of a saturated potassium sodium tartrate solution (2600 ml), and stirred at room temperature overnight. After liquid separation, the aqueous layer was extracted with n-heptane (600 ml × 3), and then the organic layer was extracted with a 5% sodium bicarbonate solution (800 ml × 4). The organic layer was concentrated under reduced pressure to obtain compound 8a as a yellow oil, 135.0 g, yield 94.5%, HPLC purity 95.0%, 4.2% of the diastereoisomer at the cyano position, dr = 23:1.

[0125] LCMS[M+H] + 430,[M-H] - 428。

[0126] 1 H NMR(400MHz,Chloroform-d)δ7.39–7.28(m,10H),5.29–5.16(m,4H),5.13–5.07(m,1H),3.78–3.63(m,2H),3.14(p,J=7.8Hz,1H),2.67(ddd,J=12.7,8.7,2.7Hz,1H),2.50(dd,J=16.8,7.6Hz,1H),2.19–1.94(m,3H),1.78(dd,J=12.7,7.8Hz,1H),1.02(t,J=7.4Hz,3H).

[0127] Example 3:

[0128]

[0129] At room temperature, Et3Al (2M hexane solution, 5 ml, 9.97 mmol, 3 eq.) and TMSCN (1.25 ml, 9.97 mmol, 3 eq.) were added to 10 ml toluene and refluxed at 110°C for 1 h. Then, compound 7a (1.338 g, 3.32 mmol, 1 eq.) obtained in Example 1 and TMSCN (2.5 ml, 19.9 mmol, 6 eq.) were added to the above solution in sequence at room temperature and stirred at 55-65°C for 1 h. The temperature was lowered to 5 to -5°C, saturated sodium bicarbonate solution (5 ml) was slowly added dropwise, and then saturated sodium potassium tartrate solution (30 ml) was added and stirred at room temperature overnight. After separation, the aqueous layer was extracted with n-heptane and ethyl acetate (4:1) (10 ml×3), and then the organic layer was extracted with 5% sodium bicarbonate solution (10 ml×4). The organic layer was concentrated under reduced pressure to obtain compound 8a as a yellow oil, 1.22 g, yield 85.4%, HPLC purity 94.0%, diastereoisomer 4.4%, dr=21:1.

[0130] Embodiment 4:

[0131]

[0132] Compound 8a (12.4 g, 28.9 mmol, 1 eq.) obtained in Example 2 was dissolved in anhydrous ethanol (37 ml). Potassium hydroxide ethanol solution (0.5 M, 57.8 ml, 28.9 mmol, 1 eq.) was added to the above solution in an oil bath at 100-110°C and reacted at this temperature for 7 h. The insoluble matter was filtered and the residue was washed with anhydrous ethanol (40 ml). Potassium hydroxide aqueous solution (1 M, 28.9 ml, 28.9 mmol, 1 eq.) was added to the obtained solution and stirred at room temperature for 2 h.

[0133] After ethanol was evaporated, it was extracted with DCM (50 ml x 2). The obtained aqueous layer was adjusted to pH 2.0 with 1M hydrochloric acid, then extracted with DCM (80 ml x 3), the organic layers were combined and concentrated under reduced pressure to obtain 6.1 g of an oily substance, the HPLC purity of which was 91.8%, 3.8% of diastereomers, and dr = 24:1. The oily substance (6.1 g) was dissolved in 5 ml of anhydrous acetonitrile, then stirred at -20°C overnight, filtered, and white crystals were obtained, 4.64 g, with a yield of 78.3%, HPLC purity of 99.1%, 0.33% of diastereomers, and dr = 300:1.

[0134] LCMS [MH] - 204.

[0135] 11H NMR (400 MHz, Chloroform-d) δ 8.63 (brs, 1H) 5.27 (s, 1H), 3.80–3.63 (m, 1H), 3.14 (p, J = 7.7 Hz, 1H), 2.80–2.69 (m, 1H), 2.67 (d, J = 2.1 Hz, 2H), 2.52 (dd, J = 16.8, 7.7 Hz, 1H), 2.14 (d, J = 7.5 Hz, 2H), 2.05 (d, J = 16.9 Hz, 1H), 1.73 (dd, J = 12.6, 7.7 Hz, 1H), 1.08 (t, J = 7.5 Hz, 3H).

[0136] Note: The 1H NMR data of the obtained key intermediate 2 is consistent with that in Patent CN104755456B.

[0137] Example 5:

[0138]

[0139] Solid potassium hydroxide (KOH, 1.62 g, 28.87 mmol, 1 eq.) was added to 95 ml of ethanol. After the KOH was completely dissolved, the compound 8a (12.4 g, 28.9 mmol, 1 eq.) obtained in Example 3 was added, and the mixture was refluxed at 85 - 95 °C for 7 h. An aqueous KOH solution (1 M, 28.9 ml, 28.9 mmol, 1 eq.) was added to the resulting solution, and the mixture was stirred at room temperature for 2 h.

[0140] After evaporating the ethanol, the mixture was extracted with DCM (50 ml × 2). The resulting aqueous layer was adjusted to pH 2.0 with 1 M hydrochloric acid, and then extracted with DCM (80 ml × 3). The organic layers were combined and concentrated under reduced pressure to obtain 6.4 g of an oil. The HPLC purity of this oil was 92.1%, the diastereoisomer was 3.5%, and dr = 26:1. The oil (6.4 g) was dissolved in 5 ml of anhydrous acetonitrile, and then stirred at -20 °C overnight. After filtration, 4.8 g of white crystals were obtained, with a yield of 81.0%, an HPLC purity of 99.3%, a diastereoisomer of 0.31%, and dr = 290:1.

[0141] Example 6:

[0142]

[0143] Potassium hydroxide solid (KOH, 3.24 g, 57.8 mmol, 1 eq.) was added to 1,4-dioxane and water (4:1, 190 ml). After the KOH was completely dissolved, compound 8a (24.8 g, 57.8 mmol, 1 eq.) was added, and the mixture was refluxed at 85 - 95 °C for 7 h. An aqueous KOH solution (1 M, 57.8 ml, 1 eq.) was added to the resulting solution, and the mixture was stirred at room temperature for 2 h.

[0144] After evaporating methanol, the mixture was extracted with DCM (100 ml × 2). The resulting aqueous layer was adjusted to pH 2.0 with 1 M hydrochloric acid, and then extracted with DCM (160 ml × 3). The organic layers were combined and concentrated under reduced pressure to obtain 9.8 g of an oily substance. The HPLC purity of this oily substance was 83.9%, the diastereoisomer was 7.6%, and dr = 11:1. 1 g of this oily substance was dissolved in 1 ml of anhydrous acetonitrile, and then stirred at -20 °C overnight, filtered to obtain 0.76 g of white crystals. The purification yield was 76.0%, the HPLC purity was 98.8%, the diastereoisomer was 0.35%, and dr = 282:1.

[0145] Example 7

[0146] The above-mentioned oily substance was prepared with reference to Example 6. The above-mentioned oily substance (4.0 g) was left at room temperature for 15 days to obtain oily substance B (4.0 g), with the purity reduced to 52.0%, the diastereoisomer 7.4%, and dr = 7:1. 1 g of this oily substance B was dissolved in 1 ml of anhydrous acetonitrile, and then stirred at -20 °C overnight, filtered to obtain 0.42 g of white crystals. The purification yield was 42.0%, the HPLC purity was 88.9%, the diastereoisomer was 1.1%, and dr = 81:1.

[0147] Example 8:

[0148]

[0149] Anhydrous THF (2 L) was added to a 5 L jacketed flask. After cooling to 5 - -5 °C, TiCl4 (160 ml, 1.468 mol, 2 eq.) was injected, and the mixture was stirred at this temperature for 15 min; then compound 3 (100 g, 0.734 mol, 1 eq.) and compound 11 (177.8 g, 0.807 mol, 1.1 eq.) were added to the jacketed flask, and the mixture was stirred at this temperature for 2 h. Pyridine (236 ml, 2.937 mol, 4 eq.) was added to the above reaction solution, and the mixture was stirred at this temperature for 2 h, and then the reaction was carried out overnight. 1 L of water was added to quench this reaction. After liquid separation, the aqueous layer was extracted with n-heptane and ethyl acetate (4:1) (1 L × 4). The organic layer was washed with saturated brine (400 ml) and concentrated under reduced pressure to obtain compound 7b as a yellow oily substance, 248.4 g, with a yield of 100% and an HPLC purity of 93.4%.

[0150] 1 1H NMR (400 MHz, Chloroform-d) δ 5.43–5.32 (m, 1H), 4.39–4.18 (m, 5H), 3.68–3.53 (m, 4H), 3.40–3.27 (m, 7H), 2.89 (q, J = 6.7 Hz, 1H), 2.78–2.60 (m, 2H), 2.21 (ddd, J = 16.6, 3.9 Hz, 1H), 2.09 (q, J = 7.5 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H)

[0151] Example 9:

[0152]

[0153] At room temperature, Et3Al (2 M n-hexane solution, 1 L, 2 mol, 3 eq.) and TMSCN (748.6 ml, 6 mol, 9 eq.) were added to a 5 L jacketed flask and stirred at 65 - 75 °C for 1 h. Then at room temperature, compound 7b (225 g, 666 mmol, 1 eq.) obtained in Example 8 was added to the above solution and stirred at 55 - 65 °C for 1 h. The temperature was lowered to 5 - -5 °C, and saturated sodium bicarbonate solution (1 L) was slowly added dropwise. Then the reaction mixture was added to saturated potassium sodium tartrate solution (5.2 L) and stirred at room temperature overnight. After liquid separation, the aqueous layer was extracted with n-heptane (1.2 L × 3), and then the organic layer was extracted with 5% sodium bicarbonate solution (1.6 L × 4). The organic layer was concentrated under reduced pressure to obtain compound 8b as a yellow oil, 237.5 g, yield 97.7%, HPLC purity 95.2%, diastereoisomer 3.9%, dr = 24:1.

[0154] 1 1H NMR (400 MHz, Chloroform-d) δ 5.26 (d, J = 2.0 Hz, 1H), 4.42–4.23 (m, 4H), 3.79–3.68 (m, 2H), 3.65–3.52 (m, 4H), 3.36 (d, J = 0.7 Hz, 6H), 3.15 (p, J = 7.7 Hz, 1H), 2.72 (ddd, J = 12.7, 8.7, 2.8 Hz, 1H), 2.58–2.46 (m, 1H), 2.20–1.99 (m, 3H), 1.81 (dd, J = 12.8, 7.9 Hz, 1H), 1.07 (t, J = 7.4 Hz, 3H).

[0155] Example 10:

[0156]

[0157] Potassium hydroxide solid (KOH, 30 g, 534.9 mmol, 1.1 eq.) was added to 1.6 L of ethanol. After the KOH was completely dissolved, the compound 8b (177.7 g, 486.3 mmol, 1 eq.) obtained in Example 9 was added, and the mixture was refluxed at 85 - 95 °C for 7.5 h. An aqueous KOH solution (1 M, 486.3 ml, 486.3 mmol, 1 eq.) was added to the resulting solution, and the mixture was stirred at room temperature for 2 h.

[0158] After distilling off the ethanol, 500 ml of water was added, and the mixture was extracted with DCM (1 L × 2). The resulting aqueous layer was adjusted to pH 2.0 with 1 M hydrochloric acid, and then extracted with DCM (1 L × 3). The organic layers were combined and concentrated under reduced pressure to obtain 93.2 g of an oily substance. The HPLC purity of this oily substance was 91.5%, the diastereoisomer was 3.2%, and dr = 28:1. The oily substance (93.2 g) was dissolved in 200 ml of anhydrous acetonitrile, and then stirred at -20 °C overnight. After filtration, white crystals (Compound 2), 74.5 g, were obtained. The crystallization yield was 80.0%, the HPLC purity was 99.0%, the diastereoisomer was 0.48%, and dr = 206:1.

[0159] Compound 2 prepared in this example: LCMS [M-H] - 204.

[0160] Compound 2 prepared in this example had the same retention time on HPLC as Compound 2 prepared in Example 4.

[0161] Comparative Example 1

[0162] The oily substance (1 g) obtained in Example 6 was dissolved in 18 ml of anhydrous acetonitrile, and then R-(+)-1-phenylethylamine (0.31 ml) was added. The mixture was stirred at room temperature overnight, and after filtration, 0.47 g of white crystals were obtained. The salt formation yield was 29.5%, the HPLC purity was 85.9%, the diastereoisomer was 0.95%, and dr = 90:1.

[0163] Comparative Example 2

[0164] The oily substance (1 g) obtained in Example 6 was dissolved in 10 ml of toluene, and then benzylamine (0.53 ml) was added. The mixture was stirred at room temperature overnight, and no solid precipitated.

[0165] Comparative Example 3

[0166] The oily substance B (1 g) obtained in Example 7 was dissolved in 5 ml of anhydrous acetonitrile, and then R-(+)-1-phenylethylamine (0.62 ml) was added. The mixture was stirred at room temperature overnight, filtered, and 0.45 g of white solid was obtained. The salt formation yield was 28.4%, the HPLC purity was 70.1%, the diastereoisomer was 2.5%, and dr = 28:1.

[0167] Comparative Example 4

[0168] The oily substance B (1 g) obtained in Example 7 was dissolved in 5 ml of toluene, and then benzylamine (0.52 ml) was added. The mixture was stirred at room temperature overnight, and no solid was precipitated.

[0169] Comparative Example 5

[0170] The oily substance (1 g) obtained in Example 6 was dissolved in a mixed solution of anhydrous acetonitrile and water (4:1, 1 ml), and then the mixture was stirred at -20 °C overnight, and no solid was precipitated.

[0171] Comparative Example 6

[0172] The oily substance (1 g) obtained in Example 6 was dissolved in 1 ml of isopropanol, and then the mixture was stirred at -20 °C overnight, and no solid was precipitated.

[0173] Comparative Example 7

[0174]

[0175] At room temperature, triethylaluminum (Et3Al, 2 M n-hexane solution, 5 ml, 10 mmol, 3 eq.) and trimethylsilyl cyanide (TMSCN, 3.75 ml, 30 mmol, 9 eq.) were added to a schlenk tube and stirred at 65 - 75 °C for 1 h. Then, at room temperature, compound 4 (0.925 g, 3.33 mmol, 1 eq.) was added to the above solution and stirred at 55 - 65 °C for 1 h. The temperature was lowered to 5 - -5 °C, and saturated sodium bicarbonate solution (5 ml) was slowly added dropwise, and then saturated potassium sodium tartrate solution (26 ml) was added. The mixture was stirred at room temperature overnight. After liquid separation, the aqueous layer was extracted with n-heptane (6 ml × 3), and then the organic layer was extracted with 5% sodium bicarbonate solution (10 ml × 4). The organic layer was concentrated under reduced pressure to obtain compound 5 as a yellow oily substance, 0.86 g, with a yield of 84.7%, an HPLC purity of 85.5%, a diastereoisomer of 11.3%, and dr = 7.6:1.

Claims

1. A method for preparing compound 2, characterized in that, It includes the following steps: in acetonitrile, crude compound 2 is crystallized to obtain compound 2; The temperature of the crystallization is -10 to -30 °C.

2. The preparation method of compound 2 as described in claim 1, characterized in that, The preparation method satisfies one or more of the following conditions: (1) The temperature of the crystallization is -10, -15, -20, -25 or -30 °C; (2) The time of the crystallization is 1 to 20 hours; (3) The mass-volume ratio of crude compound 2 to acetonitrile is 1:(0.2 to 10); the mass-volume ratio is g:mL; (4) The purity of crude compound 2 is 50 to 98%; (5) The content of the diastereomeric compound 2' in the crude product of the compound 2 is 1 to 10%; and (6) The dr value of crude compound 2 is 30:1 to 5:

1.

3. The preparation method of compound 2 as claimed in claim 2, characterized in that, The preparation method satisfies one or more of the following conditions: (1) The time of the crystallization is 2, 4, 6, 8, 10 or 12 hours; (2) The mass-volume ratio of crude compound 2 to acetonitrile is 1:(0.5 to 2); the mass-volume ratio is g:mL; (3) The purity of crude compound 2 is 91.8%, 92.1%, 83.9%, 52.0%; (4) The content of the diastereoisomer compound 2' in the crude product of the compound 2 is 2-8%; and ​ (5) The dr value of crude compound 2 is 26:1, 24:1, 11:1 or 7:

1.

4. The preparation method of compound 2 according to claim 2, characterized in that, The preparation method satisfies one or two of the following conditions: (1) The mass-volume ratio of crude compound 2 to acetonitrile is 1:1, 6.1:5 or 6.4:5; the mass-volume ratio is g:mL; (2) The content of the diastereomeric compound 2` in the crude product of the compound 2 is 3.5%, 3.8%, 7.4% or 7.6%.

5. The preparation method of compound 2 according to any one of claims 1-4, characterized in that, Crude compound 2 is prepared by the following preparation method: In a solvent, compound 8 reacts in the presence of a base to obtain crude compound 2 as follows, Among them, R 1 is benzyl, phenyl, -CH2CH2OCH3 or -CH2CH2OCH2CH2OCH3.

6. The preparation method of compound 2 as claimed in claim 5, characterized in that, The preparation method of crude compound 2 satisfies one or more of the following conditions: (1)R 1 is benzyl or -CH2CH2OCH3; (2) The solvent is an alcohol solvent, a nitrile solvent or a mixed solvent of a nitrile solvent and water; (3) The base is an inorganic strong base; (4) The molar ratio of compound 8 to the base is 1:(2 to 10); and (5) The preparation method includes the following steps: in the solvent, compound 8 reacts with an alcoholic solution of the base, and then reacts with an aqueous solution of the base to obtain crude compound 2.

7. The preparation method of compound 2 according to claim 6, characterized in that, The preparation method of crude compound 2 satisfies one or more of the following conditions: (1) The solvent is an alcohol solvent; (2) The base is an alkali metal hydroxide; and (3) The molar ratio of compound 8 to the base is 1:(2 to 4).

8. The preparation method of compound 2 as described in claim 6, characterized in that, The preparation method of crude compound 2 satisfies one or two of the following conditions: (1) The base is lithium hydroxide, sodium hydroxide or potassium hydroxide; (2) The molar ratio of compound 8 to the base is 1:

2.

9. The preparation method of compound 2 according to claim 6, wherein, The preparation method of crude compound 2 satisfies one or more of the following conditions: (1) The alcohol solvent is one or more of methanol, ethanol and isopropanol; (2) The nitrile solvent is acetonitrile; (3) The volume ratio of the nitrile solvent to water in the mixed solvent of the nitrile solvent and water is (1 - 10):1; (4) The alcoholic solution is a methanol solution, an ethanol solution and / or an isopropanol solution; (5) The concentration of the alcoholic solution of the base is 0.1 to 10 mol / L; (6) The concentration of the aqueous solution of the base is 0.1 to 10 mol / L; (7) The temperature of the reaction with the alcoholic solution of the base is 80 - 140 °C; (8) The temperature for reacting with the aqueous solution of the base is 0 - 40 °C; (9) The reaction time with the alcoholic solution of the base is 4 - 12 hours; and (10) The reaction time with the aqueous solution of the base is 1 - 6 hours.

10. The method for preparing compound 2 according to claim 6, characterized in that, The preparation method of the crude product of Compound 2 satisfies one or more of the following conditions: (1) The alcohol solvent is ethanol; (2) In the mixed solvent of the nitrile solvent and water, the volume ratio of the nitrile solvent to water is 4:1; (3) The concentration of the alcoholic solution of the base is 0.1, 0.2, 0.5, 0.7, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mol / L; (4) The concentration of the aqueous solution of the base is 0.1, 0.2, 0.5, 0.7, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mol / L; (5) The temperature for reacting with the alcoholic solution of the base is 100 - 110 °C; (6) The temperature for reacting with the aqueous solution of the base is 15 - 30 °C; (7) The reaction time with the alcoholic solution of the base is 7 hours; and (8) The reaction time with the aqueous solution of the base is 2 hours.

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