CN117756622A - Preparation method of key intermediate of sabatier - Google Patents

Preparation method of key intermediate of sabatier Download PDF

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CN117756622A
CN117756622A CN202311768534.4A CN202311768534A CN117756622A CN 117756622 A CN117756622 A CN 117756622A CN 202311768534 A CN202311768534 A CN 202311768534A CN 117756622 A CN117756622 A CN 117756622A
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compound
formula
reaction
protecting group
amino protecting
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张宪恕
肖然
史凯
张焕成
曹铭
金飞敏
杨绍波
高强
郑保富
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Anhui Haoyuan Pharmaceutical Co ltd
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Anhui Haoyuan Pharmaceutical Co ltd
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Abstract

The invention provides a preparation method of a sabatier intermediate compound III, which comprises the steps of carrying out ring-opening reaction on a compound of a formula IV and a compound of a formula V under the action of CuX, wherein the reaction formula is as follows:wherein X and X 1 Each is independently selected from Cl, br and I; the invention directly introduces chiral 2-methyl valeric acid group through chiral raw material type IV compoundThe method has the advantages of short reaction route, time saving, chiral isomer purity improvement, and simple and convenient post-treatment operation; compared with the method provided by the prior art, the method has obvious technical advantages.

Description

Preparation method of key intermediate of sabatier
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of a key intermediate (2R, 4S) -5- (biphenyl-4-yl) -4- [ (tert-butoxycarbonyl) amino ] -2-methyl pentanoic acid of sababatrole.
Background
Enkephalinase inhibitor Sha Kuba koji (sacubiril), chemical name 4- (((2 s,4 r) -1- ([ 1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopropan-2-yl) amino) -4-oxobutanoic acid, its structure is as follows:
the compound preparation Sha Kuba valsartan sodium tablet (Entresto) is a double-effect angiotensin receptor-enkephalinase inhibitor developed by Nohua corporation, and can be used for treating hypertension and heart failure. It can effectively reduce the risk of hospitalization and death of patients with chronic heart failure (NYHA class II-IV) due to heart failure.
Sha Kuba when the amino group of the key intermediate is a Boc protecting group, (2R, 4S) -5- (biphenyl-4-yl) -4- [ (tert-butoxycarbonyl) amino ] -2-methylpentanoic acid (CAS: 1012341-50-2), the structural formula is as follows:
the current technology of compound I is mainly prepared according to the synthetic route of WO2008031567A1 and WO2014032627A 1. 4-bromobiphenyl is used as a biphenyl introducing reagent, a biphenyl compound is formed by Grignard reaction and S-epichlorohydrin, and chiral amino alcohol is formed by a photo-delay reaction (Mitsunobu reaction). After oxidation of this alcohol to form an aldehyde group, the wittig reaction (Witting reaction) forms an olefinic bond and hydrolyzes the ester group. The (2R, 4S) -5- ([ 1,1 biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl pentanoic acid is obtained by metal hydrogenation catalysis. The reaction formula is as follows:
patent WO2008083967A3 discloses the construction of biphenyl groups on substrates with biphenyl-type formants after formation of amide bonds by condensation using L-pyroglutamic acid as starting material. Then, after reduction and amino protection, methyl is formed at the alpha position of pentacyclic carbonyl in chiral mode, and then the product (2R, 4S) -5- ([ l, 1-biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl pentanoic acid is formed after deprotection, ring opening and Boc amino protection. The reaction formula is as follows:
in summary, in the preparation process reported in the prior art, the preparation of the Sha Kuba yeast key chiral intermediate I is unfavorable for industrial production due to harsh reaction conditions, long synthesis route, low yield, high production cost and complicated operation. Therefore, it is necessary to develop a more convenient, economical and convenient industrial production route for the key chiral intermediate I, which is of great industrial significance.
Disclosure of Invention
The application develops a new Sha Kuba yeast intermediate synthesis route for solving the problems of long route, low yield, low chiral isomer purity, high cost and the like in the preparation of Sha Kuba yeast intermediates in the prior art. The route is simple to operate, the reaction yield is high, the use of catalysts and ligands with high cost is avoided, the chiral purity of the product is high, and the method is suitable for industrial popularization and application.
In a first aspect, the present application provides a method for preparing a compound of formula iii, comprising reacting a compound of formula iv with a compound of formula V under CuX, wherein the reaction formula is as follows:
wherein X and X 1 Each is independently selected from Cl, br and I;
as a further development of the present application, the molar ratio of the compound of formula IV to the compound of formula V is 1 (1-5), for example 1 (1-3);
as a further improvement of the present application, the molar ratio of the IV compound to CuX is 1 (0.03-0.3), such as 1 (0.03-0.2), and further such as 1:0.045;
as a further improvement of the present application, the compound of formula V, 1' -biphenyl-4-methyl magnesium halide, may be selected from any one of 1,1' -biphenyl-4-methyl magnesium chloride, 1' -biphenyl-4-methyl magnesium bromide, or 1,1' -biphenyl-4-methyl magnesium iodide, for example, 1' -biphenyl-4-methyl magnesium bromide;
as a further improvement of the present application, the CuX is selected from any one of CuI, cuBr, cuCl, for example CuI;
as a further improvement of the present application, the ring-opening reaction is performed in an organic solvent, wherein the organic solvent is at least one selected from ethers and aromatic hydrocarbons, the ethers are any one of cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, 1, 4-dioxane, propyl ether, isopropyl ether, diethyl ether, ethylene glycol dimethyl ether or anisole, and the aromatic hydrocarbons are any one of toluene or xylene;
as a further improvement of the present application, the volume amount (mL) of the organic solvent is 1 to 10 times, for example 5 to 8 times, the mass amount (g) of the compound of formula IV; in some embodiments of the present application, the volume amount (mL) of the organic solvent is 5 times the mass amount (g) of the compound of formula iv;
as a further improvement of the present application, the ring-opening reaction temperature is-30 to 0 ℃, for example-25 to-15 ℃; the reaction time is 1 to 24 hours, for example 1 to 12 hours; in some embodiments of the present application, the reaction temperature is-25 to-15 ℃ and the reaction time is 1h;
in some embodiments of the present application, there is provided a process for preparing a compound of formula iii comprising:
1) Adding bromoethane and magnesium scraps in an inert atmosphere, dropwise adding about 1/20 part of tetrahydrofuran solution of 4-bromomethyl biphenyl at 45-55 ℃, and continuously keeping 45-55 ℃ to dropwise add the tetrahydrofuran solution of the 4-bromomethyl biphenyl with the residual amount of about 19/20 after confirming initiation;
2) Continuously stirring and reacting for 1 hour after the dripping is finished, cooling to-15 to-25 ℃, adding cuprous iodide, continuously dripping tetrahydrofuran solution of the compound IV, and carrying out heat preservation and stirring for 1 hour at-15 to-25 ℃ after the dripping is finished to obtain the compound of the formula III.
As a further development of the present application, the ring-opening reaction gives the compound of formula iii by simple isolation;
the separation step is not particularly limited in this application, and a separation step known in the art may be employed as long as the object of the present invention can be achieved. For example, the separation step may include, but is not limited to: quenching, extraction, washing, drying, concentration, recrystallization, filtration, and the like. The solvent used in the separation step may be a conventional solvent known in the art.
In some embodiments of the present application, the compound of formula III may optionally be subjected to a post-treatment comprising slowly pouring the reaction solution into dilute hydrochloric acid after completion of the ring-opening reaction, and stirring at 10-30℃for 0.5h. And then adding ethyl acetate into a reaction bottle for extraction, extracting a water phase with ethyl acetate, merging organic phases, concentrating the organic phases to 1/5-1/2 volume under reduced pressure, cooling to 0-10 ℃, carrying out suction filtration, and drying to obtain a compound III solid.
The biphenyl compounds of the present application are obtained by methods conventional in the art, for example, the methods described in the 1,1' -biphenyl-4-methyl magnesium bromide reference journal literature (Journal of the American Chemical Society (2017), 139 (37), 13126-13140) or example 1 of the present invention.
The second aspect of the application provides a preparation method of a compound of formula I, which comprises the steps of taking the compound of formula III prepared in the first aspect of the application as a raw material, and carrying out asymmetric reductive amination reaction and amino protecting group reaction to obtain the compound of formula I;
r is any one of amino protecting groups such as tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, p-methoxybenzyl, benzyl, allyloxycarbonyl;
as a further improvement of the application, under the action of chiral ruthenium catalyst, the compound III, ammonia source and hydrogen are subjected to asymmetric reductive amination to obtain the compound of the formula II,
as a further improvement of the present application, the ammonia source is selected from one or more of ammonia gas, aqueous ammonia, ammonia solution, ammonium acetate, ammonium formate, ammonium chloride, ammonium sulfate, ammonium carbonate;
as a further improvement of the application, when the ammonia source is selected from ammonia gas solution, the ammonia source can be any one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or 1, 4-dioxane and ethyl acetate solution of ammonia gas (for example, ammonia methanol solution with the molar concentration of 4mol/L to 7 mol/L);
the molar ratio of the compound III to the ammonia source is 1:1-20;
as a further improvement of the present application, the chiral ruthenium catalysts are, for example, ru (OAc) 2 [(S)-MeO-BIPHEP]Or (S) -Ru (OAc) 2 (BINAP)；
As a further improvement of the present application, the molar ratio of the compound of formula III to the ruthenium catalyst is selected from 1:0.0001 to 0.001; for example, 1:0.0003 to 0.001, and further for example, 1:0.00035;
as a further improvement of the present application, the hydrogen pressure range is selected from 0.5 to 10MPa, preferably 1.5 to 2.5MPa;
as a further improvement of the present application, the reaction temperature of the asymmetric reductive amination is selected from 45 to 70 ℃, such as 55 to 65 ℃;
as a further improvement of the present application, the reaction time of the asymmetric reductive amination is selected from 12 to 48 hours, for example 48 hours;
as a further improvement of the present application, the asymmetric reductive amination reaction solvent is selected from any one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, for example methanol;
as a further improvement of the application, after the asymmetric reductive amination reaction is completed, the reaction solution can be optionally cooled to room temperature, after nitrogen replacement, a hydrogen chloride methanol solution is dropwise added to the reaction solution until the pH value is=2-3, the reaction solution is stirred for 1h, the reaction solution is cooled to 0-10 ℃, filtered, washed and dried, and the compound solid hydrochloride is obtained.
As a further improvement of the application, the reaction of the amino protecting group can be carried out by selecting reasonable reaction conditions through the protecting group; for example, compound II or a salt thereof, with an amino protecting group reagent under the action of a base.
As a further improvement of the application, in the reaction of the amino protecting group, the molar ratio of the compound II or salt to the amino protecting group reagent is 1:1-1.2; the reaction temperature is 50-60 ℃; the reaction time is 2-12 h;
as a further improvement of the present application, the solvent for the reaction of the upper amino protecting group is selected from one or any combination of water, methanol, ethanol, isopropanol, dichloromethane, acetonitrile, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, such as methanol and water.
As a further improvement of the present application, the base is selected from an organic base or an inorganic base, the organic base is selected from any one of triethylamine, diethylamine, pyridine, diisopropylethylamine, for example diisopropylethylamine; the inorganic base is selected from one or more of potassium phosphate, potassium acetate, potassium carbonate, potassium hydroxide, sodium phosphate, sodium acetate, sodium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, and lithium hydroxide hydrate, such as sodium hydroxide;
as a further improvement of the present application, the molar ratio of compound II to base in the reaction is 1:1.1 to 5, for example 1:2;
in some embodiments of the present application, for example, R is a Boc protecting group, and when R is a Boc amino protecting group, the amino protecting group reagent is selected from di-tert-butyl dicarbonate, the present invention provides a process for preparing a compound of formula Ia comprising:
adding methanol and water into the hydrochloride of the compound II, then adding alkali (such as sodium hydroxide), dropwise adding di-tert-butyl dicarbonate at 50-60 ℃, continuously preserving heat (such as 2 hours) after the dropwise adding, distilling and concentrating, filtering, and drying under reduced pressure to obtain the compound of the formula Ia.
In a third aspect, the present application provides a method for preparing Sha Kuba koji (sacubiril), comprising the steps of preparing a compound of formula iii according to the method of the first aspect of the present invention, and preparing Sha Kuba koji from the compound of formula iii.
In a fourth aspect, the present application provides a method for preparing sabatirol (sacubiril), comprising obtaining a compound of formula I according to the method of the second aspect of the present invention, and obtaining Sha Kuba curve from the compound of formula I.
Compared with the prior art, the invention has the beneficial technical effects that:
(1) According to the invention, the chiral raw material formula IV compound is directly introduced into the chiral 2-methyl valeric acid group, so that the reaction route is short, the time is saved, the purity of chiral isomers is improved, and the post-treatment operation is simple and convenient.
(2) The invention optimizes the process, has simple operation, high accessibility of raw materials, obviously reduces the cost and is suitable for industrial production.
(3) The inventors have found that, unexpectedly, the addition of substances such as tBuXphos ligand and the like, the products are difficult to separate, and the difficulty of separating the ligand from the substrate is increased; the invention can achieve high-yield and high-quality open-loop compound without special introduction of ligand substances such as triphenylphosphine or Xphos; the yield of the ring-opening reaction reaches 73%, and the generation of ring-opening impurities at other positions can be well avoided.
(4) The inventor also found that, by adding the CuX catalyst in the ring-opening reaction, the conversion rate and the reaction rate are both obviously improved, the reaction rate of the ring-opening reaction without adding the CuX catalyst is obviously reduced, and the conversion rate is insufficient.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound III according to the invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the compound II;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the compound Ia according to the present invention;
FIG. 4 is an HPLC chart of compound Ia according to the present invention.
Detailed Description
In order to facilitate understanding of the invention of the present application by those skilled in the art, the following describes the technical scheme of the present invention in conjunction with specific embodiments. It should be understood that these examples are not intended to limit the scope and spirit of the invention as claimed. The raw materials, reagents or solvents used in the present invention are commercially available without any particular description, and the experimental methods without specifying the specific conditions are generally carried out according to the conventional conditions in the art.
Example 1
Preparation of Compound III
Under nitrogen atmosphere, 0.2mL of bromoethane and magnesium turnings (5.04 g,0.21 mol) were added to the reaction flask, a part of a tetrahydrofuran solution (250 mL) of 4-bromomethyl biphenyl (49.4 g,0.2 mol) was added dropwise at 45 to 55℃and after confirming initiation, the remaining amount was kept dropwise at 45 to 55 ℃. After the completion of the dropwise addition, stirring and reacting for 1 hour, cooling to-15 to-25 ℃, adding cuprous iodide (1.9 g,0.01 mol), continuously dropwise adding tetrahydrofuran solution (125 mL) of compound IV (25.1 g,0.22 mol), and after the completion of the dropwise addition, carrying out heat preservation and stirring for 1 hour at-15 to-25 ℃. The reaction mixture was slowly poured into dilute hydrochloric acid (6N, 100 ml) and stirred at 10-30℃for 0.5h. Then adding ethyl acetate into a reaction bottle for extraction twice, using 200mL each time, extracting a water phase once again with 100mL of ethyl acetate, merging organic phases, washing the organic phases with 200mL of water to be neutral, concentrating the organic phases under reduced pressure to 100-150 mL, cooling to 0-10 ℃, carrying out suction filtration, and drying to obtain 41.8g of compound III white powder, wherein the yield is 73%.
Compound III nuclear magnetic data: 1 H NMR(400MHz,CDCl 3 )δ7.60-7.55(m,4H),7.44(t,J＝7.6Hz,2H),7.35(d,J＝7.3Hz,1H),7.29-7.27(d,2H),3.74(s,2H),3.13–2.88(m,2H),2.55(dd,J＝17.1,5.0Hz,1H),1.20(d,J＝7.0Hz,3H).
example 2
Preparation of Compound II hydrochloride
A solution of the compound III (15 g,53.1 mmol) obtained in example 1 and 120mL of methanolic ammonia (7 mol/L) was charged into an autoclave, the air in the autoclave was replaced, and then 15mg of Ru (OAc) was added 2 [(S)-MeO-BIPHEP]The method comprises the steps of replacing gas in a reaction kettle by hydrogen, charging hydrogen to 2+/-0.5 MPa, heating to 60+/-5 ℃ for reaction for 48 hours, cooling to room temperature, transferring the reaction liquid into a flask after nitrogen replacement, dropwise adding a hydrogen chloride methanol solution to pH=2-3, stirring for 1 hour, cooling to 0-10 ℃, filtering, washing a filter cake by a small amount of methanol, and drying to obtain 14.7g of compound II hydrochloride as off-white solid with the yield of 86.5%.
Compound II nuclear magnetic data: 1 H NMR(400MHz,MeOD)δ7.62(t,J＝7.9Hz,4H),7.44(t,J＝10.3,4.8Hz,2H),7.39–7.31(m,3H),3.60(m,J＝13.6,6.3Hz,1H),3.00(d,J＝6.9Hz,2H),2.69(m,J＝8.9,7.1,5.3Hz,1H),2.05(m,J＝14.4,9.1,5.2Hz,1H),1.73–1.63(m,1H),1.20(t,J＝6.3Hz,3H).
example 3
Preparation of Compound Ia
The hydrochloride salt of Compound II (10 g,31.3 mmol) obtained in example 2 was added to a three-necked flask, 50mL of methanol and 50mL of water were added, then sodium hydroxide (2.63 g,65.7 mmol) was added dropwise, di-tert-butyl dicarbonate (7.46 g,34.2 mmol) was added dropwise at 50-60℃and the dropwise was continued to keep the temperature for 2 hours, most of the methanol was concentrated, filtered and dried under reduced pressure to give Compound Ia as an off-white powder of 11.7g, yield 97.5% and purity 99.87%.
Compound I nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ11.98(s,1H),7.63(d,J＝7.5Hz,2H),7.56(d,J＝8.2Hz,2H),7.44(t,J＝7.6Hz,2H),7.33(t,J＝7.3Hz,1H),7.24(d,J＝8.1Hz,2H),6.71(d,J＝8.7Hz,1H),3.72–3.62(m,1H),2.68(d,J＝6.8Hz,2H),2.47–2.37(m,1H),1.74(ddd,J＝13.5,9.4,4.1Hz,1H),1.42–1.29(m,8H),1.21(s,2H),1.07(t,J＝7.6Hz,3H)。

Claims (10)

1. a preparation method of a sabatier intermediate compound III comprises the steps of carrying out a ring opening reaction on a compound shown in a formula IV and a compound shown in a formula V under the action of CuX, wherein the reaction formula is shown as follows:
wherein X and X 1 And are independently selected from Cl, br and I.
2. The method of claim 1, wherein the ring-opening reaction of the compound of formula iv with the compound of formula V satisfies one or more of the following conditions:
1) The molar ratio of the compounds of the formula IV to the compounds of the formula V is 1 (1 to 5), for example 1 (1 to 3);
2) The molar ratio of the IV compound to CuX is 1 (0.03-0.3), such as 1 (0.03-0.2), and further such as 1:0.045;
3) The CuX is selected from any one of CuI, cuBr, cuCl, such as CuI;
4) The ring-opening reaction is carried out in an organic solvent;
preferably, the organic solvent is at least one selected from ethers and aromatic hydrocarbons, wherein the ethers are any one of cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, 1, 4-dioxane, propyl ether, isopropyl ether, diethyl ether, ethylene glycol dimethyl ether and anisole, and the aromatic hydrocarbons are any one of toluene and xylene;
or preferably, the volume amount (mL) of the organic solvent is 1 to 10 times, for example 5 to 8 times, the mass amount (g) of the compound of formula IV;
5) The ring-opening reaction temperature is-30 to 0 ℃, such as-25 to-15 ℃;
6) The reaction time is 1 to 24 hours, for example 1 to 12 hours.
3. A preparation method for preparing a compound of formula I comprises the steps of taking a compound of formula III prepared in claim 1 as a raw material, and carrying out asymmetric reductive amination reaction and amino protecting group reaction to obtain the compound of formula I;
r is an amino protecting group.
4. A process according to claim 3, wherein the asymmetric reductive amination of the compound of formula iii satisfies one or more of the following conditions:
1) Under the action of a chiral ruthenium catalyst, under the conditions of a compound III, an ammonia source and hydrogen, obtaining a compound of a formula II through asymmetric reductive amination reaction;
2) The ammonia source is selected from one or more of ammonia gas, ammonia water, ammonia gas solution, ammonium acetate, ammonium formate, ammonium chloride, ammonium sulfate and ammonium carbonate;
3) When the ammonia source is selected from ammonia gas solution, the ammonia gas can be any one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or 1, 4-dioxane and ethyl acetate solution of ammonia gas; for example, an ammonia methanol solution having a molar concentration of 4mol/L to 7mol/L;
4) The molar ratio of the compound III to the ammonia source is 1:1-20;
5) Chiral ruthenium catalysts such as Ru (OAc) 2 [(S)-MeO-BIPHEP]Or (S) -Ru (OAc) 2 (BINAP)；
6) The molar ratio of the compound of the formula III to the ruthenium catalyst is selected from 1:0.0001-0.001; for example, 1:0.0003 to 0.001, and further for example, 1:0.00035;
7) The hydrogen pressure range is selected from 0.5-10 MPa, preferably 1.5-2.5 MPa;
8) The reaction temperature of the asymmetric reductive amination is selected from 45-70 ℃, such as 55-65 ℃;
9) The reaction time of the asymmetric reductive amination is selected from 12 to 48 hours, such as 48 hours;
10 The asymmetric reductive amination reaction solvent is selected from any one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane and ethyl acetate, for example methanol.
5. A method according to claim 3, wherein the reaction of the upper amino protecting group is carried out with an amino protecting group reagent under the action of a base.
6. The method according to claim 5, wherein in the reaction of the amino protecting group, the molar ratio of the compound II or salt to the amino protecting group reagent is 1:1 to 1.2;
and/or, preferably, the reaction temperature is 50 to 60 ℃;
and/or, preferably, the reaction time is 2 to 12 hours;
and/or, preferably, the solvent for the reaction of the upper amino protecting group is selected from one or any combination of water, methanol, ethanol, isopropanol, dichloromethane, acetonitrile, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, for example methanol and water.
7. The process according to claim 5, wherein when R is a Boc amino protecting group, the amino protecting group reagent is selected from di-tert-butyl dicarbonate; a process for the preparation of a compound of formula Ia comprising:
adding methanol and water into the hydrochloride of the compound II, then adding alkali, dropwise adding di-tert-butyl dicarbonate at 50-60 ℃, keeping the temperature for 2 hours after the dropwise adding, concentrating by distillation, filtering, and drying under reduced pressure to obtain the compound of the formula Ia.
8. The preparation method according to one of claims 5 to 7, characterized in that the base is selected from organic or inorganic bases, the organic base being selected from any one of triethylamine, diethylamine, pyridine, diisopropylethylamine, such as diisopropylethylamine; the inorganic base is selected from one or more of potassium phosphate, potassium acetate, potassium carbonate, potassium hydroxide, sodium phosphate, sodium acetate, sodium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, and lithium hydroxide hydrate, such as sodium hydroxide;
and/or, preferably, the molar ratio of compound II to base in the reaction is from 1:1.1 to 5, for example 1:2.
9. a process for the preparation of sabatier starter comprising obtaining a compound of formula iii according to claim 1 or 2 and preparing Sha Kuba starter from the compound of formula iii.
10. A process for the preparation of sababaqu comprising obtaining a compound of formula I according to one of claims 3 to 5 and preparing Sha Kuba qu from the compound of formula I.
CN202311768534.4A 2023-12-21 2023-12-21 Preparation method of key intermediate of sabatier Pending CN117756622A (en)

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