A process for the preparation of dextromethorphan

Abstract

The application provides a preparation method of dextromethorphan, which comprises the following steps: taking cyclohexanedione 1 as a raw material, and performing an acetonitrile group substitution reaction to obtain compound 2; performing a Villier-Michel ketone synthesis reaction on the compound 2 to obtain compound 4; performing a ketal protection on the compound 4 to obtain compound 5; performing a Robinson ring expansion reaction on the compound 5 to obtain compound 6; performing an aromatization reaction and a methylation reaction on the compound 6 to obtain compound 7; performing a ketone group deprotection on the compound 7 to obtain compound 8; performing a double bond isomerization reaction on the compound 8 to obtain compound 9; performing an acetonitrile group reduction reaction on the compound 9 to obtain compound 10; performing a lactam cyclization reaction on the compound 10 to obtain compound 11; and performing an asymmetric hydrogenation reaction on the compound 11 to obtain dextromethorphan. The application develops a new asymmetric synthesis route for preparing dextromethorphan, avoids intermediate resolution, and improves the yield.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of morphinan ring synthesis, and particularly relates to a preparation method of dextromethorphan. BACKGROUND

[0002] Dextromethorphan (3-methoxy-N-methylmorphinan), referred to as DXM, is a cough suppressant, which is the right-handed body of morphine class levorphanol methyl ether. It can be obtained in more than 140 non-prescription cough and cold preparations. Due to the availability of its targeted dose, efficacy and safety, it has surpassed codeine to become the most widely used cough suppressant.

[0003] At present, the synthesis method of dextromethorphan is mostly carried out by means of splitting and Grewe cyclization. For example, 2-(1-cyclohexenyl)ethylamine III and p-methoxyphenylacetic acid II are used as raw materials, an amide intermediate IV is formed by dehydration and condensation, and then a hexahydroisoquinoline intermediate V is generated by Bishler-Napierdsky cyclization under the action of POCl3. The compound is unstable, and 1-p-methoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline V-1 is directly obtained by catalytic hydrogenation with Raney-Ni. After methylation, N-methyl compound V-2 is obtained. The product has one chiral center, and (S)-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline VII is obtained by splitting. Then, intermediate VII-1 is obtained by Grewe cyclization under the catalysis of H3PO4, and the product dextromethorphan is obtained by further methylation. The synthesis route of the method is as follows:

[0004]

[0005] The method has the following disadvantages:

[0006] (1) In the process of Grewe cyclization reaction, the intermediate VII is affected by steric hindrance, and a by-product 3-methoxy-17-acetyl-(9α,13α,14β)-morphinan is generated; and the yield of the Grewe cyclization reaction is low; the reaction is carried out at 130-140 DEG C, the methoxy group on the benzene ring is converted into the corresponding hydroxyl group after cyclization, and further methylation treatment is required, and there are more side reactions at high temperature.

[0007] (2) The splitting of the intermediate V-2 not only greatly reduces the yield, but also is complex and tedious in operation, and a large amount of waste residue and waste liquid is generated.

[0008] (3) The reagents such as phosphorus oxychloride and concentrated phosphoric acid are used in the process route, and there are more wastes, which are not friendly to the environment. SUMMARY

[0009] In view of the deficiencies in the prior art, the present application provides a preparation method of dextromethorphan, which solves the problem of low yield caused by intermediate resolution in the prior art.

[0010] The present application aims to provide a preparation method of dextromethorphan, which comprises using cyclohexanedione 1 as a raw material, performing acetonitrile group substitution reaction to obtain compound 2, performing Michael synthesis reaction on compound 2 to obtain compound 4, performing ketal protection on compound 4 to obtain compound 5, performing Robinson ring expansion reaction on compound 5 to obtain compound 6, performing aromatization reaction and methylation reaction on compound 6 to obtain compound 7, performing ketone group deprotection on compound 7 to obtain compound 8, performing double bond isomerization reaction on compound 8 to obtain compound 9, performing acetonitrile group reduction reaction on compound 9 to obtain compound 10, performing lactam cyclization reaction on compound 10 to obtain compound 11, performing asymmetric hydrogenation reaction on compound 11 to obtain compound 12, and performing N-methylation reaction on compound 12 to obtain dextromethorphan, and the reaction process is shown as follows:

[0011]

[0012] Further, the method comprises the following steps:

[0013] S1: in the presence of a first base, nucleophilic substitution reaction occurs between cyclohexanedione and bromoacetonitrile in a first solvent to generate compound 2;

[0014] S2: Michael addition reaction occurs between compound 2 and butenone in the presence of a first catalyst to generate compound 3;

[0015] S3: asymmetric Robinson cyclization reaction occurs between compound 3 in the presence of a second catalyst and a first additive to generate compound 4;

[0016] S4: ketalization reaction occurs between compound 4 and ethylene glycol in the presence of a third catalyst and a second additive in a second solvent to generate compound 5;

[0017] S5: compound 5 is sequentially reacted with tetrahydropyrrole and butenone in a third solvent, and then subjected to reflux cyclization reaction under acidic conditions to generate compound 6;

[0018] S6: aromatization reaction occurs between compound 6 in the presence of a fourth catalyst in a fourth solvent, and then methylation reaction occurs in the presence of a second base to generate compound 7;

[0019] S7: hydrolysis reaction occurs between compound 7 in the presence of an acid in a fifth solvent to generate compound 8;

[0020] S8: Compound 8 is subjected to isomerization reaction with a tertiary butanol alkali metal salt in a sixth solvent to generate Compound 9;

[0021] S9: Compound 9 is subjected to cyano group reduction, primary amine acetylation, carbonyl group reduction and acetyl group removal under the action of a fifth catalyst, an acylating agent and a reducing agent to generate Compound 10;

[0022] S10: Compound 10 is subjected to cyclization reaction under the action of bromine in a seventh solvent, and then subjected to dehydrogen halogenation reaction in the presence of a third base to generate Compound 11;

[0023] S11: Compound 11 is subjected to stereoselective hydrogenation reaction with a hydrogen donor under the action of a sixth catalyst in an eighth solvent to generate Compound 12;

[0024] S12: Compound 12 is subjected to Eschweiler-Clarke methylation reaction under the action of formic acid and formaldehyde to generate dextromethorphan.

[0025] Further, the first base is a quaternary ammonium base, preferably, the first base is benzyltrimethylammonium hydroxide, the second base is potassium carbonate, and the third base is sodium carbonate.

[0026] Further, the first solvent is methanol and water, the second solvent is dichloromethane, the third solvent is toluene, the fourth solvent is acetonitrile, the fifth solvent is a mixed solution of dichloromethane and water, the sixth solvent is tertiary butanol, the seventh solvent is dichloromethane, and the eighth solvent is methanol.

[0027] Further, the first catalyst is triethylamine; the second catalyst is (S)-N1,N1-diethyl-3,3-dimethyl-1,2-butanediamine and trifluoromethanesulfonic acid; the third catalyst is trimethylsilyl trifluoromethanesulfonate, the fourth catalyst is bromination ketone, the fifth catalyst is Raney Ni, and the sixth catalyst is palladium hydroxide.

[0028] Further, the first additive is m-nitrobenzoic acid; and the second additive is triethyl orthoformate.

[0029] Further, the acid is oxalic acid.

[0030] Further, the tertiary butanol alkali metal is potassium tert-butoxide, the acylating agent is acetic anhydride, and the hydrogen donor is ammonium formate.

[0031] Further, the reducing agent is hydrazine hydrate.

[0032] Further, the molar ratio of cyclohexanedione: bromoacetonitrile: the first base is 1:1:0.4; the molar ratio of compound 2: butenone: the first catalyst is 1:1:0.01; in step S3, the molar ratio of compound 3: the second catalyst: the first additive is 1:0.1:0.05; the molar ratio of compound 4: ethylene glycol: the third catalyst: the second additive is 1:5.5:0.02:1.1; the molar ratio of compound 5: butenone: tetrahydropyrrole is 1:1.05:1.2; the molar ratio of compound 6: the fourth catalyst is 1:0.05; the molar ratio of compound 7: acid is 1:3.2; the molar ratio of compound 8: tert-butyl alcohol alkali salt is 1:1; the molar ratio of compound 9: the fifth catalyst: acylating agent: reducing agent is 1:0.1:1.05:1.1; the molar ratio of compound 10: bromine: the third base is 1:1:2; the molar ratio of compound 11: the sixth catalyst: hydrogen donor is 1:0.1:5; the molar ratio of compound 12: formaldehyde is 1:2; the amount ratio of compound 12: formic acid is 0.3:4 in g / ml.

[0033] In an embodiment of the present application, in step S1, the reaction temperature is room temperature, and the reaction time is 20-24 h.

[0034] In an embodiment of the present application, in step S2, the reaction temperature is room temperature, and the reaction time is 2-3 h.

[0035] In an embodiment of the present application, in step S3, the reaction temperature is room temperature, and the reaction time is 2-3 h.

[0036] In an embodiment of the present application, in step S4, the reaction temperature is -15 to -10℃, and the reaction time is 5-7 h.

[0037] In an embodiment of the present application, in step S5, the reaction temperature is 110-115℃, and the reaction time is 16-20 h.

[0038] In an embodiment of the present application, in step S6, the reaction temperature is room temperature, and the reaction time is 16-20 h.

[0039] In an embodiment of the present application, in step S7, the reaction temperature is room temperature, and the reaction time is 2-5 h.

[0040] In an embodiment of the present application, in step S8, the reaction temperature is 20-25℃, and the reaction time is 2-4 h.

[0041] In an embodiment of the present application, in step S9, the cyanide reduction and primary amine acetylation temperature is room temperature, and the reaction time is 6-8 h; the carbonyl reduction temperature is 160-180℃, and the reaction time is 6-8 h.

[0042] In one embodiment of the present application, in step S10, the cyclization reaction temperature is 0-5℃, and the cyclization reaction time is 0.5-1h; the dehydrohalogenation reaction temperature is 135-150℃, and the reaction time is 1-1.5h.

[0043] In one embodiment of the present application, in step S11, the reaction temperature is 135-145℃, and the reaction time is 5-7h.

[0044] In one embodiment of the present application, in step S12, the reaction temperature is 70-100℃, and the reaction time is 2-4h.

[0045] Compared with the prior art, the present application has the following beneficial effects:

[0046] (1) The present application develops a new asymmetric synthesis route to prepare dextromethorphan, avoids intermediate resolution, improves the yield, improves the atomic economy, and reduces waste.

[0047] (2) The new synthesis route of the present application does not use expensive starting materials, and the reaction conditions are relatively mild, which is conducive to industrialized production.

[0048] (3) The present application avoids harsh process conditions, greatly reduces the three wastes, and is environmentally friendly. DETAILED DESCRIPTION

[0049] The technical solutions in the present application will be further described below in combination with examples.

[0050] Example 1 Preparation of 3-(2,6-dioxocyclohexyl)acetonitrile (compound 2)

[0051]

[0052] In a standard glass bottle, cyclohexanedione (900 mg, 8.03 mmol), bromoacetonitrile (8.03 mmol, 1.0 eq.), benzyltrimethylammonium hydroxide (3.21 mmol, 0.4 eq.) were dissolved in 10 ml of a mixture of methanol and water in a volume ratio of 20:1, and the reaction was carried out at room temperature for 24 h; methanol was concentrated, the residue was added into isopropyl acetate, washed with water, dried, and concentrated to obtain compound 2 (840 mg) with a yield of 70%.

[0053] Example 2 Preparation of compound 3

[0054]

[0055] In a standard glass bottle, compound 2 (5 g, 33.08 mmol), methyl vinyl ketone (33.08 mmol, 1.0 eq.), 1% triethylamine (TEA, 335 mg) were added and the reaction was carried out at 25 °C under solvent free conditions for 2 h. Compound 3 (7.32 g) was obtained with 100% yield.

[0056] Example 3 Preparation of compound 4

[0057]

[0058] To compound 3 (2.0 g, 9.04 mmol) was added catalyst (S)-N1,N1-diethyl-3,3-dimethyl-1,2-butanediamine trifluoromethanesulfonic acid (0.9 mmol, 0.1 eq.), m-NO2C6H4CO2H (0.45 mmol, 0.05 eq.) and the reaction was carried out at room temperature under solvent free conditions for 2 h. The reaction mixture was separated by chromatography to obtain compound 4 (1.66 g) with 90% yield and 96% enantioselectivity.

[0059] Example 4 Preparation of compound 5

[0060]

[0061] To compound 4 (2.0 g, 9.84 mmol), 1,2-ethanediol (54.12 mmol, 5.5 eq.) and dichloromethane 20 ml were added to a reaction flask along with trifluoromethylsilicane trimethylsilicane (TMSOTf, 0.2 mmol, 0.02 eq.) and triethyl orthoformate (10.82 mmol, 1.1 eq.) and the reaction was carried out at -10 °C for 5 h to obtain compound 5 (2.16 g) with 89% yield.

[0062] Example 5 Preparation of compound 6

[0063]

[0064] To tetrahydropyrrole (4.37 mmol, 1.2 eq.) and toluene 20 ml were added in a standard glass bottle and compound 5 (900 mg, 3.64 mmol) was added dropwise and the reaction was carried out at 110-115 °C under reflux for 6 h after which methyl vinyl ketone (4.37 mmol, 1.05 eq.) was added and the reaction was carried out at 110-115 °C under reflux for 5 h. The organic phase was separated and concentrated. The concentrate was taken in a mixture of acetic acid and water in the ratio 2:1, 8 ml and the reaction was carried out at 100 °C under reflux for 5 h, separated and distilled under reduced pressure to obtain compound 6 (0.71 g) with 65% yield.

[0065] Example 6 Preparation of compound 7

[0066]

[0067] Compound 6 (800 mg, 2.67 mmol) and copper bromide (0.14 mmol, 0.05 eq.) were dissolved in acetonitrile 10 ml in a standard glass bottle and the aromatization reaction was carried out at room temperature for 13 h, after which time iodomethane (3.47 mmol, 1.3 eq.) and potassium carbonate (3.47 mmol, 1.3 eq.) were added and the reaction was carried out at room temperature for 3 h, obtaining compound 7 (0.774 g) with a yield of 93%.

[0068] Example 7. Preparation of (R)-2-(6-methoxy-2-oxo-2,3,4,4a,9,10- hexahydrophenanthren-4a-yl)acetonitrile (compound 8)

[0069]

[0070] Compound 7 (1.0 g, 3.21 mmol), oxalic acid (10.28 mmol, 3.2 eq.) were added in a 1:1 mixture of water and dichloromethane (DCM) 10 ml in a standard glass bottle and the reaction was carried out at room temperature for 2 h, obtaining compound 8 (729 mg) with a yield of 85% after column chromatography.

[0071] Example 8. Preparation of (S)-2-(6-methoxy-2-oxo-1,2,3,4,4a,9- hexahydrophenanthren-4a-yl)acetonitrile (compound 9)

[0072]

[0073] Compound 8 (850 mg, 3.18 mmol) and potassium tert-butoxide (3.18 mmol, 1 eq.) were added in tert-butanol 8 ml in a standard glass bottle and the isomerization reaction was carried out at room temperature for 2 h, obtaining compound 9 (638 mg) with a yield of 75%.

[0074] Example 9. Preparation of (S)-2-(6-methoxy-1,2,3,4,4a,9- hexahydrophenanthren-4a-yl)ethylamine (compound 10)

[0075]

[0076] In a standard glass bottle, compound 9 (1.0 g, 3.74 mmol), THF 10 mL, Raney Ni (0.37 mmol, 0.1 eq.), acetic anhydride (3.93 mmol, 1.05 eq.) were added, hydrogen was replaced and the reaction was carried out at 25 °C for 6 h. After that, it was filtered and the filtrate was concentrated, diethyleneglycol diethyl ether 10 mL, hydrazine hydrate (4.11 mmol, 1.1 eq.) were added and the reaction was carried out at 180 °C for 6 h to obtain compound 10. Yield 86%.

[0077] Example 10 Preparation of compound 11

[0078]

[0079] In a solution of dichloromethane 20 ml, compound 10 (2.0 g, 7.77 mmol), bromine (7.77 mmol, 1.0 eq.) were added and the intramolecular cyclization was carried out at 0-5 °C for 0.5 h. After that, it was washed with water twice, dried and concentrated, N,N-dimethylformamide (DMF, 20 ml), sodium bicarbonate (15.54 mmol, 2.0 eq.) were added and the reaction was carried out at 135 °C for 1.0 h to obtain compound 11. Yield 73%.

[0080] Example 11 Preparation of compound 12

[0081]

[0082] In a solution of methanol 10 ml, compound 11 (500 mg, 1.96 mmol), palladium hydroxide (0.2 mmol, 0.1 eq.), ammonium formate (9.79 mmol, 5 eq.) were added and the stereoselective hydrogenation was carried out at 135 °C for 5 h to obtain compound 12. Yield 90%.

[0083] Example 12 Preparation of dextromethorphan

[0084]

[0085] In a reaction glass bottle, compound 12 (1.5 g, 5.83 mmol), formic acid 20 ml and formaldehyde (11.66 mmol, 2.0 eq.) were added and the reaction was carried out at 100 °C under reflux for 2 h to obtain dextromethorphan. Yield 95%.

[0086] Finally, it should be pointed out that the above examples are merely intended to illustrate the technical solutions of the present application and not to limit it, and although the present application has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present application can be modified or equivalently replaced without departing from the purpose and scope of the technical solutions of the present application, and they should all be covered in the scope of the claims of the present application.

Claims

1. A process for the preparation of dextromethorphan, characterized by: The preparation process comprises the following steps: compound 2 is obtained by nucleophilic substitution reaction of cyclohexanone and bromoacetonitrile in a first solvent in the presence of a first base; compound 3 is obtained by Michael addition reaction of compound 2 and butenone in the presence of a first catalyst; compound 4 is obtained by asymmetric Robinson cyclization reaction of compound 3 in the presence of a second catalyst and a first additive; compound 5 is obtained by ketalization reaction of compound 4 and ethylene glycol in a second solvent in the presence of a third catalyst and a second additive; compound 6 is obtained by reaction of compound 5 with tetrahydropyrrole and butenone in a third solvent, and then by reflux cyclization reaction under acidic conditions; compound 7 is obtained by aromatization reaction of compound 6 in a fourth solvent in the presence of a fourth catalyst, and then by methylation reaction in the presence of a second base; compound 8 is obtained by hydrolysis reaction of compound 7 in a fifth solvent in the presence of an acid; compound 9 is obtained by isomerization reaction of compound 8 with a tertiary butanol alkali metal salt in a sixth solvent; compound 10 is obtained by cyano group reduction, primary amine acetylation, carbonyl reduction and acetyl group removal of compound 9 in the presence of a fifth catalyst, an acylating agent and a reducing agent; compound 11 is obtained by cyclization reaction of compound 10 in the presence of bromine, and then by dehydrohalogenation reaction in the presence of a third base; compound 12 is obtained by stereoselective hydrogenation reaction of compound 11 in an eighth solvent in the presence of a sixth catalyst; dextromethorphan is obtained by Eschweiler-Clarke methylation reaction of compound 12 in the presence of formic acid and formaldehyde. The preparation process comprises the following steps: compound 2 is obtained by nucleophilic substitution reaction of cyclohexanone and bromoacetonitrile in a first solvent in the presence of a first base; compound 3 is obtained by Michael addition reaction of compound 2 and butenone in the presence of a first catalyst; compound 4 is obtained by asymmetric Robinson cyclization reaction of compound 3 in the presence of a second catalyst and a first additive; compound 5 is obtained by ketalization reaction of compound 4 and ethylene glycol in a second solvent in the presence of a third catalyst and a second additive; compound 6 is obtained by reaction of compound 5 with tetrahydropyrrole and butenone in a third solvent, and then by reflux cyclization reaction under acidic conditions; compound 7 is obtained by aromatization reaction of compound 6 in a fourth solvent in the presence of a fourth catalyst, and then by methylation reaction in the presence of a second base; compound 8 is obtained by hydrolysis reaction of compound 7 in a fifth solvent in the presence of an acid; compound 9 is obtained by isomerization reaction of compound 8 with a tertiary butanol alkali metal salt in a sixth solvent; compound 10 is obtained by cyano group reduction, primary amine acetylation, carbonyl reduction and acetyl group removal of compound 9 in the presence of a fifth catalyst, an acylating agent and a reducing agent; compound 11 is obtained by cyclization reaction of compound 10 in the presence of bromine, and then by dehydrohalogenation reaction in the presence of a third base; compound 12 is obtained by stereoselective hydrogenation reaction of compound 11 in an eighth solvent in the presence of a sixth catalyst; dextromethorphan is obtained by Eschweiler-Clarke methylation reaction of compound 12 in the presence of formic acid and formaldehyde. ； The preparation process comprises the following steps: compound 2 is obtained by nucleophilic substitution reaction of cyclohexanone and bromoacetonitrile in a first solvent in the presence of a first base; compound 3 is obtained by Michael addition reaction of compound 2 and butenone in the presence of a first catalyst; compound 4 is obtained by asymmetric Robinson cyclization reaction of compound 3 in the presence of a second catalyst and a first additive; compound 5 is obtained by ketalization reaction of compound 4 and ethylene glycol in a second solvent in the presence of a third catalyst and a second additive; compound 6 is obtained by reaction of compound 5 with tetrahydropyrrole and butenone in a third solvent, and then by reflux cyclization reaction under acidic conditions; compound 7 is obtained by aromatization reaction of compound 6 in a fourth solvent in the presence of a fourth catalyst, and then by methylation reaction in the presence of a second base; compound 8 is obtained by hydrolysis reaction of compound 7 in a fifth solvent in the presence of an acid; compound 9 is obtained by isomerization reaction of compound 8 with a tertiary butanol alkali metal salt in a sixth solvent; compound 10 is obtained by cyano group reduction, primary amine acetylation, carbonyl reduction and acetyl group removal of compound 9 in the presence of a fifth catalyst, an acylating agent and a reducing agent; compound 11 is obtained by cyclization reaction of compound 10 in the presence of bromine, and then by dehydrohalogenation reaction in the presence of a third base; compound 12 is obtained by stereoselective hydrogenation reaction of compound 11 in an eighth solvent in the presence of a sixth catalyst; dextromethorphan is obtained by Eschweiler-Clarke methylation reaction of compound 12 in the presence of formic acid and formaldehyde. The first base is a quaternary ammonium base, the second base is potassium carbonate, and the third base is sodium carbonate; The first catalyst is triethylamine; the second catalyst is (S)-N1,N1-diethyl-3,3-dimethyl-1,2-butanediamine and trifluoromethanesulfonic acid; the third catalyst is trimethylsilyl trifluoromethanesulfonate, the fourth catalyst is bromoform, the fifth catalyst is Raney-Ni, and the sixth catalyst is palladium hydroxide. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The first additive is m-nitrobenzoic acid; the second additive is triethyl orthoformate.

2. A process for the preparation of dextromethorphan as claimed in claim 1, wherein: The first solvent is methanol and water, the second solvent is dichloromethane, the third solvent is toluene, the fourth solvent is acetonitrile, the fifth solvent is a mixed solution of dichloromethane and water, the sixth solvent is tert-butyl alcohol, the seventh solvent is dichloromethane, and the eighth solvent is methanol.

3. A process for the preparation of dextromethorphan as claimed in claim 1, wherein: The acid is oxalic acid.

4. A process for the preparation of dextromethorphan as claimed in claim 1, wherein: The tert-butyl alcohol alkali metal is potassium tert-butoxide, the acylating agent is acetic anhydride, and the hydrogen donor is ammonium formate.

5. A process for the preparation of dextromethorphan as claimed in claim 1 wherein: The reducing agent is hydrazine hydrate.

6. A process for the preparation of dextromethorphan as claimed in claim 1 wherein: The molar ratio of cyclohexanone: bromoacetonitrile: the first base is 1:1:0.4; the molar ratio of compound 2: butenone: the first catalyst is 1:1:0.01; in step S3, the molar ratio of compound 3: the second catalyst: the first additive is 1:0.1:0.05; the molar ratio of compound 4: ethylene glycol: the third catalyst: the second additive is 1:5.5:0.02:1.1; the molar ratio of compound 5: butenone: tetrahydropyrrole is 1:1.05:1.2; the molar ratio of compound 6: the fourth catalyst is 1:0.05; the molar ratio of compound 7: acid is 1:3.2; the molar ratio of compound 8: the tert-butyl alcohol alkali metal salt is 1:1; the molar ratio of compound 9: the fifth catalyst: the acylating agent: the reducing agent is 1:0.1:1.05:1.1; the molar ratio of compound 10: bromine: the third base is 1:1:2; the molar ratio of compound 11: the sixth catalyst: the hydrogen donor is 1:0.1:5; the molar ratio of compound 12: formaldehyde is 1:2; the ratio of the amount of compound 12: formic acid is 0.3:4 in g / ml.

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