CN113121342A - Preparation method and application of shakubiqu intermediate - Google Patents
Preparation method and application of shakubiqu intermediate Download PDFInfo
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- CN113121342A CN113121342A CN201911421091.5A CN201911421091A CN113121342A CN 113121342 A CN113121342 A CN 113121342A CN 201911421091 A CN201911421091 A CN 201911421091A CN 113121342 A CN113121342 A CN 113121342A
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Abstract
The invention discloses a preparation method and application of a shakubiqu intermediate. The shakubiqu intermediate is prepared by taking itaconic anhydride as a raw material, performing manual reduction, esterification, selective hydrolysis and carboxyl activation, and finally coupling with 4-biphenylacetic acid; the invention also provides a method for preparing the shakubiqu by using the shakubiqu intermediate. The preparation method has the advantages of easily available raw materials, simple process, economy, environmental protection and the like, and is more suitable for industrial production compared with other routes.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a preparation method of a shakubiqu intermediate and application of the shakubiqu intermediate.
Background
Sabotabiqu (Sacubitril), chemically known as 4- (((2S,4R) -1- ([1, 1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoic acid, having the following structural formula:
the Entresto chinese common name shakubitrezavapsartan sodium tablet is first approved by the FDA to be marketed by adults with chronic heart failure with reduced ejection fraction in 2015 for 7 months to reduce the risk of cardiovascular death and heart failure hospitalization, and is considered to be one of the most important pounds in new medicines marketed by novartis in recent years. Entresto is a novel anti-heart failure drug with double inhibitory effects of enkephalinase/angiotensin receptors, and comprises ARB (valsartan) and an enkephalinase inhibitor (sacubitril), wherein the ARB (valsartan) can improve vasodilatation and stimulate the body to excrete water and sodium; the enkephalinase inhibitor (sacubitril) has the function of reducing blood pressure, and has better clinical performance than the prior medicine due to the double action mechanisms.
For the preparation of Sacubitril (Sacubitril), some methods for its preparation are disclosed in the prior patent literature.
In patent WO2008031567a1 a method for the preparation of 4-amino substituted felbinac and derivatives thereof and further for the preparation of shakubitrex is disclosed. In the patent, 2-amino substituted biphenylpropanol is used as a raw material, is oxidized into aldehyde and undergoes a witting reaction to obtain 4-amino substituted biphenylbutenoic acid and derivatives thereof, and then is reduced and subjected to chiral resolution by using a metal catalyst and a chiral ligand to obtain 4-amino substituted biphenylacetic acid and derivatives thereof. The 4-amino substituted felbinac and derivatives thereof can be further used for preparing the shakubitrex. An exemplary reaction is as follows:
patent WO2008083967AA2 discloses a method for preparing shakubiqu from 2-carbonylproline as a raw material through carboxyl activation, biphenyl substitution, carbonyl reduction to methylene, chiral methylation, ring-opening reaction and amidation, wherein the exemplary reaction formula is as follows:
in CN104556700A, a method for preparing shakubiqu by using chiral induction reagent (S) -1- (α -aminobenzyl) -2-naphthol as raw material, performing cyclization reaction with 2R-methyl-4-oxo-butyric acid, and performing addition, debenzylation, ring opening, esterification, amidation and other reaction steps is disclosed, and an exemplary reaction formula is as follows:
in CN106977415A, a method for preparing shakubiqu by using 4-biphenylacetic acid as a raw material, coupling with diethyl malonate derivative to obtain beta-keto ester, and further performing coupling, decarboxylation, amination and amidation reactions is disclosed, and an exemplary reaction formula is as follows:
although the starting materials and the reaction route are different, the methods for preparing the shakubiqu have the defects of difficult acquisition of chiral starting materials, various reaction steps, high price of chiral reduction catalysts or chiral induction reagents, repeated protection and deprotection of carboxyl and amino and the like, and are not beneficial to industrial production.
Disclosure of Invention
Compared with the prior art for preparing the shakubiqu, the invention provides the method which is more beneficial to the industrial preparation of the shakubiqu.
In order to realize the purpose of the invention, the invention provides a preparation method of a shakubiqu intermediate and a method for preparing shakubiqu by using the shakubiqu intermediate.
The invention adopts a technical scheme that: a preparation method of a shakubiqu intermediate takes itaconic anhydride as a raw material, and a compound shown in a formula (01) is obtained by chiral reduction with a chiral metal catalyst in the presence of hydrogen; esterifying the compound of the formula (01) under the condition of an acid catalyst to obtain a compound of a formula (02); in the presence of lipase, selectively hydrolyzing a compound shown in a formula (02) in a phosphate solution to obtain a mono-acid type (03) compound; activating carboxyl of the compound of the formula (03) to obtain a compound of a formula (04); under the existence of strong alkali, the compound of the formula (04) and 4-biphenylacetic acid are coupled to obtain a compound of the formula (05), namely a key intermediate of the Sacubitril; the synthetic route of the above reaction is as follows:
further, taking itaconic anhydride as a raw material, and carrying out chiral reduction in an organic solvent in the presence of hydrogen and a metal catalyst and a chiral ligand to obtain a compound shown in a formula (01); the metal catalyst is a transition metal element of groups 7, 8 or 9 in the periodic table of chemical elements, preferably ruthenium; the chiral ligand is any one of (R) -Segphos, (S) -Segphos, Josiphos, (R) -BINAP, (S) -BINAP, Binapine, (Rc, Sp) -Duanphos, Walphos, (R, R) -Me-Duphos and (S, S) -Me-Duphos, and preferably (S, S) -Me-Duphos.
Further, the molar weight ratio of the chiral metal catalyst to itaconic anhydride is 1:100-1:10000, preferably 1:1000, parts by weight; the pressure of the hydrogen is 0.1-10MPa, preferably 5 MPa; the organic solvent is any one of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran and toluene, preferably ethyl acetate. The ee value of the compound of formula (01) obtained in this step is > 99%.
Further, the compound of formula (01) is reacted and esterified in alcohol solution under the condition of acid catalyst to obtain the compound of formula (02).
Further, R in the compound of formula (02)1Is any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and benzyl; the acid catalyst is any one of concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, thionyl chloride and oxalyl chloride, and concentrated sulfuric acid is preferred; the dosage of the acid catalyst is 0.1-1.0 equivalent, preferably 0.1 equivalent; the alcoholic solution is methanol, ethanol, isopropanol,Any one of n-butanol, tert-butanol and benzyl alcohol, preferably ethanol; the temperature required for the esterification reaction is 20 to 200 ℃ and preferably 80 ℃.
Further, the lipase is any one of porcine pancreatic lipase, porcine liver lipase, LipaseAK, LipaseAS, LipaseAYS, LipasePS, LipaseM, LipaseG, Lipolase100L, LipozymeCALLB, LipozymeRMIM, LipozymeTLTM, Novozyme435 lipase and Palatise 20000L, preferably LipozymeCALLB; the mass ratio of the lipase to the compound shown as the formula (02) is 0.1-1: 1, preferably 0.2: 1; the temperature required for the selective hydrolysis reaction is 20-60 ℃, preferably 25 ℃; the phosphate solution is any one of sodium dihydrogen phosphate/disodium hydrogen phosphate buffer solution and potassium dihydrogen phosphate/dipotassium hydrogen phosphate buffer solution; the pH value of the phosphate solution is 1-9, preferably 7; the volume/mass ratio of the phosphate solution to the compound of formula (02) is 5:1 to 100:1, preferably 20: 1.
further, the compound of the formula (03) is activated and reacted with an activating reagent in an organic solvent to obtain a compound of the formula (04), wherein R in the compound of the formula (04)2Is any one of chlorine, bromine, methanesulfonic acid group, trifluoromethanesulfonyl group and p-toluenesulfonyl group.
Further, the activating reagent is any one of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus tribromide, methanesulfonic anhydride, trifluoromethanesulfonic anhydride and p-toluenesulfonic anhydride, and oxalyl chloride is preferred; the molar weight ratio of the activating reagent to the compound of the formula (03) is 1:1-5:1, preferably 1.5: 1; the organic solvent is any one of ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, acetonitrile, N-hexane, N-dimethylformamide and dimethyl sulfoxide, and the N-hexane is preferred.
Further, under the condition of strong alkali, the compound of the formula (04) and 4-biphenylacetic acid are subjected to coupling reaction in an organic solvent to obtain the compound of the formula (05).
Further, the strong base is any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, DBU, n-butyllithium, tert-butyllithium, lithium diisopropylamide, methyl magnesium bromide, ethyl magnesium bromide, isopropyl magnesium bromide, methyl magnesium chloride, ethyl magnesium chloride, isopropyl magnesium chloride, and isopropyl magnesium chloride-lithium chloride, preferably isopropyl magnesium chloride; the molar weight ratio of said strong base to the compound of formula (04) is 1:1 to 5:1, preferably 2: 1; the molar ratio of the compound of formula (04) to 4-biphenylacetic acid is 1: 1-1:5, preferably 1: 1; the organic solvent is any one of ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, acetonitrile, N-dimethylformamide and dimethyl sulfoxide, and tetrahydrofuran is preferred; the coupling reaction temperature is-80 ℃ to 80 ℃, preferably-80 ℃.
The other technical scheme adopted by the invention is as follows: the application of the shakubiqu intermediate for preparing the shakubiqu adopts the shakubiqu intermediate, and comprises the following steps:
a) the compound of formula (06) is prepared by taking the compound of formula (05) as a starting material through an enzyme catalytic reaction,
b) preparing a compound of formula (07) from a compound of formula (06);
c) the compound of formula (07) and succinic anhydride are subjected to amidation condensation reaction in the presence of a base to prepare the Sacubitril.
Further, the enzyme-catalyzed reaction is carried out in the presence of transaminase and pyridoxal phosphate in a mixed solution of water and an organic solvent.
Furthermore, the transaminase is any one of 64 transaminases purchased from biomedicines of the family Shangkong, and is numbered A1-A8, B1-B8, C1-C8, D1-D8, E1-E8, F1-F8, G1-G8 and H1-H8.
Further, the compound of formula (07) prepared in step b) is prepared by hydrolyzing the compound of formula (06) to acid, and then performing esterification reaction with ethanol under acidic conditions.
The compound of formula (07) and succinic anhydride are subjected to amidation condensation reaction in the presence of alkali to prepare the Sacubitril. The preparation method is disclosed in the prior patents, such as WO2008031567A1 and CN104556700A, which are well known to those skilled in the art.
Compared with the existing method for preparing the Sacubiqu, the preparation method of the key intermediate of the Sacubiqu and the method for preparing the Sacubiqu by using the intermediate have the characteristics of cheap and easily-obtained raw materials, simple process, environmental protection, economy and the like, and are beneficial to industrial production of the Sacubiqu.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail by referring to the following examples. The described embodiments are only some, not all embodiments of the invention.
Examples
Preparation of R-methyl succinic anhydride (1)
Itaconic anhydride (50g, 446.4mmol) and ethyl acetate (250ml) were added to a 500ml hydrogenation vessel, argon was bubbled for 10min, (S, S) -Me-Duphos (136.6mg, 0.45mmol) and p-cymene ruthenium dichloride (275.6mg, 0.45mmol) were added, (S, S) -Me-Duphos (136.6mg, 0.45mmol) and hydrogen was pressurized to 5MPa, the reaction was carried out at 35 ℃ for 24h, TLC detection was complete, concentration was carried out to 100ml, a white solid precipitated, and suction filtration was carried out to dryness to give 1 as a white solid (49.3 g%, yield 96.9%).
1HNMR(500MHz,CDCl3)δ3.25–3.14(m,2H),2.68–2.59(m,1H),1.45(d,J＝9.0Hz,3H).MS(ESI)m/z:115.1[M+H]+。
Synthesis of R-ethylmethylsuccinate (2)
A500 ml single-neck flask was charged with R-methylsuccinic anhydride (49.3g, 432.5mmol) and ethanol (200ml), and 5ml of concentrated sulfuric acid was added and heatedThe reaction was refluxed for 24h, and the reaction was checked by TLC to completion. Spin-drying the solvent, adding ethyl acetate and water, separating to obtain organic phase, washing with dilute sodium bicarbonate solution, washing with water, drying, and spin-evaporating to remove the solvent to obtain colorless oily substance 2(76g, 93.4%, ee value)>99％)。1HNMR(500MHz,CDCl3)δ4.18–4.11(m,4H),2.95–2.86(m,1H),2.76–2.69(m,1H),2.42–2.37(m,1H),1.28–1.21(m,9H).MS(ESI)m/z:189.2[M+H]+。
Preparation of R-4-ethoxy-3-methyl-4-oxobutanoic acid (3)
To a 2000ml Erlenmeyer flask were added R-ethylmethylsuccinate (76g, 404mmol) and phosphate buffer (1520ml, pH 7.0), lipase (15.2g, 20% wt) was added, and the reaction was stirred at room temperature. Gas phase detection to completion, pH 1 adjusted with 5N sulfuric acid solution, extraction with ethyl acetate (300 ml. times.3), combined organic phases, water washed dry and rotary evaporated to remove solvent to give 3 as a colorless oil (55g, 85%, purity > 99%).
1HNMR(500MHz,CDCl3)δ4.15(q,J＝9Hz,2H),3.00–2.91(m,1H),2.76–2.70(m,1H),2.46–2.40(m,1H),1.26(t,J＝8.5Hz,6H).MS(ESI)m/z:161.17[M+H]+。
Preparation of R-4-chloro-2-methyl-4-oxobutanoic acid ethyl ester (4)
R-4-ethoxy-3-methyl-4-oxobutanoic acid (55g, 343.6mmol) and n-hexane (200ml) were added to a 500ml single-necked flask, oxalyl chloride (44ml, 515.4mmol) was added dropwise under ice-water bath, the reaction was stirred at room temperature, and TLC was performed until completion of the reaction. The solvent was removed by rotary evaporation to give 4(60.1g) as a colorless oil.
Preparation of ethyl (R) -5- ([1, 1' -biphenyl ] -4-yl) -2-methyl-4-pentanoate (5)
4-Biphenylacetic acid (71.4g,336.5mmol) and tetrahydrofuran (150ml) were added to a 2000ml three-necked flask, cooled to 0 ℃ and isopropyl magnesium chloride (517.7ml, 673mmol, 1.3mol/LinTHF) was slowly added dropwise to the flask, warmed to room temperature and stirred for 1 h. Cooled to-40 ℃ and 4(60.1g, 336.5mmol) was dissolved in tetrahydrofuran (50ml) and added slowly dropwise to the reaction. After the dropwise addition, the reaction is carried out for 24 hours at room temperature, TLC detection is carried out until the reaction is complete, ethyl acetate and water are added, liquid separation is carried out to obtain an organic phase, and the organic phase is washed by water, dried and dried. Column chromatography (PE: EA 15:1) gave 5 as a pale yellow solid (88.7g, 85% yield over two steps).
1HNMR(500MHz,CDCl3)δ7.65(t,J＝7.5Hz,4H)，7.50(t,J＝8.0Hz,2H)，7.35(t,J＝7.5Hz,1H)，7.25(d,J＝8.5Hz,2H)，4.10(q,J＝9Hz,2H),3.85(s,2H),3.05–2.98(m,2H),2.46–2.40(m,1H).MS(ESI)m/z:311.4[M+H]+。
Preparation of ethyl (2R,4S) -5- ([1, 1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate (6)
Isopropylamine (50g) was dissolved in H2O (50ml), adjusted to pH 7.5-8.0 with aqueous hydrochloric acid, dimethyl sulfoxide (125ml) was added, and then diluted to 500ml with 0.1M tris (hydroxymethyl) aminomethyl-hydrochloric acid buffer. The mixture was heated to 35 ℃ and transaminase (5g) and pyridoxal phosphate (4g, 18.8mmol) were added. Mixing (R) -5- ([1, 1' -biphenyl)]-4-yl) -2-methyl-4-pentanoic acid ethyl ester (50g, 161mmol) was dissolved in dimethyl sulfoxide (125ml) and slowly added dropwise to the buffered solution containing transaminase. Controlling the pH value to 7.5-8.0 by using 20% isopropylamine aqueous solution in the reaction process, keeping the temperature to 35-40 ℃ for reaction for 24h, detecting by TLC (thin layer chromatography) until the reaction is complete, filtering to remove solids, extracting mother liquor by ethyl acetate for 3 times, combining organic phases, washing by water, drying and spin-drying to obtain a light yellow solid 6(45.1g, yield 90.1%, dr value>99％)。
1HNMR(500MHz,CDCl3)δ8.60(s，2H),7.55(dd,J＝14.5,7.5Hz,4H)，7.45(t,J＝8.0Hz,2H)，7.35-7.25(m,3H)，4.10(q,J＝9Hz,2H),3.75(s,1H),3.45–3.30(m,1H),2.85(dd,J＝20.5,9.5Hz,2H)，2.15–2.05(m,1H),1.85–1.75(m,1H),MS(ESI)m/z:312.4[M+H]+。
7. Preparation of shakubiqu
Adding (2R,4S) -5- ([1, 1' -biphenyl) into a 500ml three-necked bottle]-4-yl) -4-amino-2-methyl ethyl valerate (15.5g, 50mmol), pyridine (12g, 150mmol) and dichloromethane (250ml), stirring at room temperature until the mixture is dissolved, adding succinic anhydride (10g, 100mmol), heating to 40 ℃ -45 ℃, reacting for 6h, supplementing succinic anhydride (5g, 50mmol), continuing to react for 6h, checking by TLC until the reaction is complete, concentrating under reduced pressure to remove the solvent, heating the residual solid with an ethyl acetate/n-hexane mixed solution until the solution is dissolved, slowly cooling to room temperature to precipitate the solid, and performing suction filtration and drying to obtain white solid shakubiqu (16.1g, yield 78.1%).1HNMR(500MHz,DMSO)δ7.96(d,J＝8.5Hz,1H)，7.62(d，J＝7.0Hz，2H),7.55(d，J＝8.0Hz，2H),7.45(t,J＝8.0Hz,2H)，7.30(t,J＝7.5Hz,1H)，7.25(d,J＝8.5Hz,2H)，4.02-3.86(m,3H),2.75(dd,J＝13.5,6.5Hz,1H)，2.64(dd,J＝12.5,6.5Hz,1H)，2.50–2.45(m,1H),2.25(dd,J＝23.5,7.5Hz,4H)，1.80–1.65(m,1H),1.47–1.35(m,1H),1.10(t,J＝7.5Hz,3H),1.04(d,J＝7.0Hz,3H)，MS(ESI)m/z:412.2[M+H]+。
Claims (11)
1. A preparation method of a shakubiqu intermediate is characterized in that itaconic anhydride is used as a raw material, and a compound of a formula (01) is obtained by chiral reduction with a chiral metal catalyst in the presence of hydrogen; esterifying the compound of the formula (01) under the condition of an acid catalyst to obtain a compound of a formula (02); in the presence of lipase, selectively hydrolyzing a compound shown in a formula (02) in a phosphate solution to obtain a mono-acid type (03) compound; activating carboxyl of the compound of the formula (03) to obtain a compound of a formula (04); under the existence of strong alkali, the compound of the formula (04) and 4-biphenylacetic acid are coupled to obtain a compound of the formula (05), namely a key intermediate of the Sacubitril; the synthetic route of the above reaction is as follows:
r in the Compound of formula (02)1Is any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and benzyl.
2. The method for preparing the shakubitrex intermediate according to claim 1, wherein the metal catalyst is a transition metal element in groups 7, 8 or 9 of the periodic table of chemical elements; the chiral ligand is any one of (R) -Segphos, (S) -Segphos, Josiphos, (R) -BINAP, (S) -BINAP, Binapine, (Rc, Sp) -Duanphos, Walphos, (R, R) -Me-Duphos and (S, S) -Me-Duphos; the molar weight ratio of the chiral metal catalyst to the itaconic anhydride is 1:100-1: 10000.
3. The preparation method of the shakubitqu intermediate as claimed in claim 1, wherein the compound of formula (01) is reacted and esterified in an alcohol solution under the condition of an acidic catalyst to obtain a compound of formula (02); the acidic catalyst is any one of concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, thionyl chloride and oxalyl chloride; the dosage of the acidic catalyst is 0.1-1.0 equivalent; the alcoholic solution is any one of methanol, ethanol, isopropanol, n-butanol, tert-butanol and benzyl alcohol.
4. The method of claim 1, wherein the lipase is any one of porcine pancreatic lipase, porcine liver lipase, LipaseAK, LipaseAS, LipaseAYS, LipasePS, LipaseM, LipaseG, Lipolase100L, LipozymeCALB, LipozymeRMIM, LipozymeTLTM, Novozyme435 lipase, Palatase 20000L.
5. The method for preparing the shakubitrex intermediate according to claim 1, wherein the compound of formula (03) is reacted with a living organic solventActivating and reacting with a chemical reagent to obtain a compound of formula (04), wherein R in the compound of formula (04)2Is any one of chlorine, bromine, methanesulfonic acid group, trifluoromethanesulfonyl group and p-toluenesulfonyl group.
6. The preparation method of the shakubiqu intermediate as claimed in claim 5, wherein the activating reagent is any one of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus tribromide, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-toluenesulfonic anhydride; the molar weight ratio of the activating reagent to the compound of the formula (03) is 1:1-5: 1; the organic solvent is any one of ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, acetonitrile, N-dimethylformamide and dimethyl sulfoxide.
7. The preparation method of the shakubitril intermediate as claimed in claim 1, characterized in that the compound of formula (04) and 4-biphenylacetic acid are subjected to coupling reaction in an organic solvent in the presence of a strong base to obtain the compound of formula (05).
8. The method for preparing the shakubitril intermediate according to claim 7, wherein the strong base is any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, DBU, n-butyllithium, tert-butyllithium, lithium diisopropylamide, methyl magnesium bromide, ethyl magnesium bromide, isopropyl magnesium bromide, methyl magnesium chloride, ethyl magnesium chloride, isopropyl magnesium chloride and isopropyl magnesium chloride-lithium chloride; the molar weight ratio of the strong base to the compound of formula (04) is 1:1-5: 1; the molar weight ratio of the compound of formula (04) to 4-biphenylacetic acid is 1: 1-1: 5; the organic solvent is any one of ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, acetonitrile, N-dimethylformamide and dimethyl sulfoxide.
9. The application of the Sacubitril intermediate obtained by the preparation method of any one of claims 1-8, wherein the Sacubitril intermediate is used for preparing Sacubitril, and the preparation method comprises the following steps:
a) the compound of formula (06) is prepared by taking the compound of formula (05) as a starting material through an enzyme catalytic reaction,
wherein R is1Is any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and benzyl;
b) preparing a compound of formula (07) from a compound of formula (06);
c) the compound of formula (07) and succinic anhydride are subjected to amidation condensation reaction in the presence of a base to prepare the Sacubitril.
10. The use according to claim 9, wherein the enzyme-catalyzed reaction is carried out in the presence of a transaminase and pyridoxal phosphate; the transaminase is any one of 64 transaminases which are purchased from biological medicines of Shangke and are numbered A1-A8, B1-B8, C1-C8, D1-D8, E1-E8, F1-F8, G1-G8 and H1-H8.
11. The use according to claim 9, wherein the compound of formula (07) is prepared in step b) by hydrolysis of the compound of formula (06) to acid followed by esterification with ethanol under acidic conditions.
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