CN110054563A - The Preparation Method And Their Intermediate of butyrolactone compound - Google Patents
The Preparation Method And Their Intermediate of butyrolactone compound Download PDFInfo
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- CN110054563A CN110054563A CN201910497888.7A CN201910497888A CN110054563A CN 110054563 A CN110054563 A CN 110054563A CN 201910497888 A CN201910497888 A CN 201910497888A CN 110054563 A CN110054563 A CN 110054563A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/303—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of Preparation Method And Their Intermediates of butyrolactone compound, specifically disclose a kind of preparation method of compound 7.The preparation method yield is higher, it is easy to operate, be suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of Preparation Method And Their Intermediates of butyrolactone compound.
Background technique
Bu Waxitan (Brivaracetam), entitled (the 2S) -2- [(4R) -2- oxo -4- propyl -1- pyrrolidinyl] of chemistry
Butyramide is third generation antiepileptic when Belgium is excellent than company's research and development, obtains EMEA and FDA respectively in January, 2016 and 2 months
Approval listing, for treating the breaking-out of adult and 16 years old or more teenager epileptic part, with or without secondary complete
The adjuvant treatment of body breaking-out.
Butyrolactone compound 7 (- 2 (3H) -one of (R) -4- propyl dihydrofuran) can be used as the pass of synthesis Bu Waxitan
Key intermediate.
Kosugi, H et al. (J.Chem.Soc.Perkin Trans.I., 1989,935-943) report a compound
7 synthetic route.The route restores to obtain cis-form olefin using chiral sulfoxide as starting material through metal rhodium catalysis, after in zinc powder
It is catalyzed lower and trichloro-acetic chloride cyclization, then dechlorinated and desulfurization obtains product, not only starting material is not easy to buy this method, and uses
The metal tin catalyst very big to valuable metal rhodium catalyst and toxicity, therefore it is unsuitable for industrialized production.
The synthesis road of the compound 7 of Mukaiyama, T et al. (Chemistry Letters., 1980,635-638) report
Line obtains asymmetric lactone through addition, methylation, removing and hydrolysis using chiral heptatomic ring as starting material.But it should
Route, as starting material, is not easy commercialization purchase, and generate more by-product, atom economy not only with complicated intermediate
Property is poor, therefore is unsuitable for industrialized production.
The conjunction of the compound 7 of Chamberlin, R et al. (J.Org.Chem., 1993,58 (10), 2725-2737) report
It is prepared in chirality using disubstituted chiral oxazoline ketone and bromoacetyl chloride as starting material through the reaction of seven steps at route
The mercury reagent of severe toxicity is also used in ester, final step, and route is long and environmental pollution is serious, therefore is unsuitable for industrialized production.
CN107759539A discloses a kind of synthetic route of compound 7:
The synthetic route includes following steps:
(1) positive valeric acid is reacted under the action of lithium diisopropylamine with bromoacetate, is obtained after column chromatographic purifying
2- (2- ethyoxyl -2- oxoethyl) valeric acid, step yield 42%-51%；
(2) the chiral phenyl ethylamine of 2- (2- ethyoxyl -2- oxoethyl) valeric acid is split, obtains chipal compounds (R) -2-
(2- ethyoxyl -2- oxoethyl) valeric acid, step yield 28%-35%；
(3) by (R) -2- (2- ethyoxyl -2- oxoethyl) valeric acid through BH3It restores, obtains (R) -3- after column chromatographic purifying
(methylol) ethyl hexanoate, step yield 67%-78%；
(4) (R) -3- (methylol) ethyl hexanoate is subjected under p-methyl benzenesulfonic acid cyclization, obtains compound 7, it should
Walk yield 50%-60%；
Wherein step 1 and 2 yields are lower, and step 1 and 3 needs to chromatograph using column, step 2 chiral resolution Atom economy
Difference loses the raw material of more than half, is unfavorable for industrialized production.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of preparation method of new butyrolactone compound and wherein
Mesosome, the preparation method yield is higher, it is easy to operate, be suitable for industrialized production.
The present invention provides a kind of preparation methods of compound 5 comprising following steps: in organic solvent, by chemical combination
Catalytic hydrogenation as follows is carried out under the conditions of object 4 is existing for the catalyst, obtains the compound 5；
The catalyst is [Rh ((Sc, Rp)-Duanphos) (X)]+Y-, wherein X is NBD or COD, Y BF4、PF6
Or SbF6；
R is methyl or ethyl；
In some embodiments, R is methyl.
In some embodiments, in the catalytic hydrogenation, the catalyst is [Rh ((Sc, Rp)-
Duanphos)(NBD)]+BF4 -。
In the catalytic hydrogenation, the organic solvent can be the Conventional solvents of this field the type reaction,
Such as alcohols solvent (such as methanol), ether solvent (such as tetrahydrofuran), esters solvent and halogenated hydrocarbon solvent (such as dichloro
Methane) one of or it is a variety of.In some embodiments, the organic solvent is methanol.
In the catalytic hydrogenation, the dosage of the organic solvent can be the routine of this field the type reaction
The volume mass ratio of dosage, example organic solvent as mentioned and the compound 4 is 5-15mL/g (such as 10mL/g).
In the catalytic hydrogenation, the dosage of the catalyst can be used for the conventional of this field the type reaction
Amount, the molar ratio of example catalyst as mentioned and the compound 4 be 0.0005:1-0.5:1 (such as 0.001:1-0.01:
1, such as 0.001:1).
The reaction temperature of the catalytic hydrogenation can be the ordinary temperature of this field the type reaction, such as 10-
50 DEG C (such as 15-25 DEG C).
The process of the catalytic hydrogenation can be used in this field traditional test methods (such as TLC, HPLC, GC or
NMR it) is monitored, as reaction end when generally no longer being reacted using compound 4.In some embodiments, the catalysis
The reaction time of hydrogenation can be 8-16 hours.
After the completion of the catalytic hydrogenation, post-processing step can further include.The post-processing step
It can be the conventional post-processing step of this field the type reaction, such as: after fully reacting, it is concentrated to get crude product, crude product warp
Product is obtained after vacuum distillation.
The preparation method of the compound 5 can further include following steps: compound 3 and R-OH are existed
SOCl2In the presence of carry out esterification as follows, obtain the compound 4；
In the esterification, the R-OH can be used as solvent and reactant simultaneously.
In the esterification, the dosage of the R-OH can be the conventional amount used of this field the type reaction, example
The volume mass ratio of R-OH as mentioned and the compound 3 is 5-15mL/g (such as 8-12mL/g, such as 10mL/g).
In the esterification, the SOCl2Dosage can for this field the type reaction conventional amount used, example
SOCl as mentioned2It is 0.1:1-1:1 (such as 0.35:1-0.45:1, such as 0.4:1) with the molar ratio of the compound 3.
The reaction temperature of the esterification can be the ordinary temperature of this field the type reaction, such as 0-10 DEG C.
The traditional test methods (such as TLC, HPLC, GC or NMR) in this field can be used in the process of the esterification
It is monitored, as reaction end when generally no longer being reacted using compound 3.In some embodiments, the esterification
Reaction time can be 2-3 hours.
After the completion of the esterification, post-processing step can further include.The post-processing step can be with
For the conventional post-processing step of this field the type reaction.In some embodiments, the post-processing step includes: reaction
After the completion, reaction solution is concentrated under reduced pressure to give crude product lower than 30 DEG C, normal heptane mashing filters, and obtains after filtration cakes torrefaction described
3 product of compound.
In some embodiments, in the esterification, the volume mass of the R-OH and the compound 3
Than for 8-12mL/g；The SOCl2Molar ratio with the compound 3 is 0.4:1；The reaction of the esterification
Temperature is 0-10 DEG C.
In some embodiments, the esterification includes the following steps: SOCl2Instill compound 3 and R-OH
Mixture in, 0-10 DEG C of stirring after fully reacting, is concentrated under reduced pressure to give crude product lower than 30 DEG C, and normal heptane mashing filters, filter
Product is obtained after biscuit is dry.
The present invention also provides a kind of preparation methods of compound 6 comprising following steps:
(1) compound 5 is prepared in the preparation method of compound 5 as described above；
(2) in organic solvent, by the compound 5 in BH3In the presence of carry out reduction reaction as follows, obtain
To the compound 6；
In the reduction reaction, the organic solvent can be the Conventional solvents of this field the type reaction, such as
The mixed solvent of tetrahydrofuran and dimethyl sulphide.The volume ratio of the tetrahydrofuran and dimethyl sulphide can be 5:1-10:1
(such as 8:1-9:1).
In the reduction reaction, the dosage of the organic solvent can be used for the conventional of this field the type reaction
The volume mass ratio of amount, example organic solvent as mentioned and the compound 5 is 5-15mL/g (such as 8-12mL/g).
In the reduction reaction, the BH3Dosage can for this field the type reaction conventional amount used, such as
The BH3It is 1.1:1-4:1 (such as 1.8:1-2.5:1, such as 2:1-2.2:1) with the molar ratio of the compound 5.
The reaction temperature of the reduction reaction can be the ordinary temperature of this field the type reaction, such as 5-30 DEG C
(such as 5-15 DEG C, such as 10 DEG C).
The traditional test methods (such as TLC, HPLC, GC or NMR) in this field can be used in the process of the reduction reaction
It is monitored, as reaction end when generally no longer being reacted using compound 5.In some embodiments, the reduction reaction
Reaction time can be 8-16 hours.
After the completion of the reduction reaction, post-processing step can further include.The post-processing step can be with
For the conventional post-processing step of this field the type reaction.In some embodiments, the post-processing step includes: reaction
After completely, the reaction of 1N hydrochloric acid, ethyl acetate extraction, organic phase is washed, dry and concentrate after obtain crude product, be directly used in
It reacts in next step.
In some embodiments, in the reduction reaction, the volume ratio of the tetrahydrofuran and dimethyl sulphide is
8-9:1；The BH3Molar ratio with the compound 5 is 2:1-2.2:1；The reaction temperature of the reduction reaction is
5-15℃。
In some embodiments, the reduction reaction includes the following steps: compound 5, BH3, tetrahydrofuran and
The mixture of dimethyl sulphide is stirred at 5-15 DEG C, after fully reacting, the reaction of 1N hydrochloric acid, and ethyl acetate extraction, organic phase warp
Washing obtains crude product after drying and concentrating, and is directly used in and reacts in next step.
The present invention also provides a kind of preparation methods of compound 7 comprising following steps:
(1) compound 6 is prepared in the preparation method of compound 6 as described above；
(2) in a solvent, the compound 6 is subjected in the presence of HCl cyclization as follows, obtains institute
The compound 7 stated；
In the cyclization, the solvent can be the Conventional solvents of this field the type reaction, such as tetrahydro
The mixed solvent of furans and water.The volume ratio of the tetrahydrofuran and water can be 0.8:1-1.2:1 (such as 1:1).
In the cyclization, the dosage of the solvent can be the conventional amount used of this field the type reaction, example
The volume mass ratio of solvent as mentioned and the compound 6 is 5-15mL/g (such as 8-12mL/g).
In the cyclization, the dosage of the HCl can be the conventional amount used of this field the type reaction, such as
The molar ratio of the HCl and the compound 6 are 2:1-3:1 (such as 2.6:1-2.7:1).
The reaction temperature of the cyclization can be the ordinary temperature of this field the type reaction, such as 15-25 DEG C.
The traditional test methods (such as TLC, HPLC, GC or NMR) in this field can be used in the process of the cyclization
It is monitored, as reaction end when generally no longer being reacted using compound 6.In some embodiments, the cyclization
Reaction time can be 2-3 hours.
In some embodiments, in the cyclization, the solvent is the mixed solvent of tetrahydrofuran and water,
The volume ratio of the tetrahydrofuran and water is 0.8:1-1.2:1, and the molar ratio of the HCl and the compound 6 are
2.6:1-2.7:1；The reaction temperature of the cyclization is 15-25 DEG C.
After the completion of the cyclization, post-processing step can further include.The post-processing step can be with
For the conventional post-processing step of this field the type reaction.In some embodiments, the post-processing step includes: reaction
After completely, ethyl acetate extraction, organic phase is washed, dry and concentrate after obtain crude product, crude product obtains product through vacuum distillation.
In some embodiments, the cyclization include the following steps: by compound 6, HCl, tetrahydrofuran and
The mixture of water stirs at 15-25 DEG C, after fully reacting, ethyl acetate extraction, organic phase is washed, dry and concentrate after
To crude product, crude product obtains 7 product of compound through being evaporated under reduced pressure.
The present invention also provides a kind of preparation methods of compound 7 comprising following steps: in a solvent, compound 6 being existed
Cyclization as follows is carried out in the presence of HCl, obtains the compound 7；R is methyl or ethyl (such as first
Base)；
In the preparation method of the compound 7, each reaction condition can be as previously described.
The present invention also provides a kind of preparation methods of compound 6 comprising following steps: in organic solvent, by chemical combination
Object 5 is in BH3In the presence of carry out reduction reaction as follows, obtain the compound 6；R is methyl or ethyl (example
Such as methyl)；
In the preparation method of the compound 6, each reaction condition can be as previously described.
The present invention also provides a kind of preparation methods of compound 4 comprising following steps: compound 3 and R-OH are existed
SOCl2In the presence of carry out esterification as follows, obtain the compound 4；R be methyl or ethyl (such as
Methyl)；
In the preparation method of the compound 4, each reaction condition can be as previously described.
The present invention also provides a kind of compounds 6:
The structure of (Sc, Rp)-Duanphos are as follows:
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: provide a kind of preparation method and wherein of new butyrolactone compound
Mesosome, the preparation method yield is higher, it is easy to operate, be suitable for industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1
Synthetic route:
Step 1:
The compound 1 of 245g is added in the acetonitrile of 2.45L, the nitropropane of 151.5g is then added dropwise, temperature control is lower than
25 DEG C, the DBU of 258.7g is then added dropwise, is stirred at room temperature 2 hours, middle control fully reacting, concentration removes acetonitrile solvent, and acetic acid is added
Ethyl ester (1L) and water (0.5L), layering, water layer are extracted twice with ethyl acetate (0.5L*2) again.Merge organic phase, with 1N hydrochloric acid
(0.25L*2) is washed twice；Saturated salt solution (0.25L) washed once, and anhydrous sodium sulfate is dry, be concentrated to get crude product 296g,
Yield 94%.
1H NMR(400MHz,CDCl3) δ 6.96 (t, J=7.5Hz, 1H), 3.74 (d, J=3.4Hz, 3H), 3.68 (s,
3H), 3.35 (s, 2H), 2.20 (m, J=7.5Hz, 2H), 1.07 (t, J=7.6Hz, 3H).
Step 2:
The compound 2 of 72.6g is added in the alcohol solvent of 1.4L, the solution of the NaOH of the 2N of 585mL is then added dropwise,
It is heated to reflux stirring 3 hours, middle control fully reacting, concentration removes most of alcohol solvent, water (200mL) and ethyl acetate is added
(200mL) layering, water phase washed once with ethyl acetate (50mL).Water phase is acidified to pH=1-2, ethyl acetate with 1N HCl
(200mL*2) is extracted twice；Merging organic phase, saturated salt solution (100mL) washing organic phase is primary, and anhydrous sodium sulfate is dry,
It is concentrated to get crude product, normal heptane (200mL) mashing filters, and drying obtains solid product 57g, yield 92.4%.
1H NMR (400MHz, DMSO) δ 12.23 (s, 2H), 6.76 (t, J=7.6Hz, 1H), 3.20 (s, 2H), 2.14
(m, J=7.5Hz, 2H), 0.98 (t, J=7.5Hz, 3H).MS[M+Na]+=181.1.
Step 3:
The compound 3 of 95g is added in the methanol solvate of 950mL, the SOCl of 29.0g is then added dropwise2(0.4eq), it is low
It is stirred 2 hours in 10 DEG C；Middle control raw material fully reacting, a little diester by-product are concentrated under reduced pressure to give crude product, positive heptan lower than 30 DEG C
Alkane (100mL) mashing overnight, filters drying and obtains product 72g, yield 70%.
1H NMR(400MHz,CDCl3) δ 7.12 (t, J=7.5Hz, 1H), 3.71 (s, 3H), 3.37 (s, 2H), 2.25 (m,
J=7.5Hz, 2H), 1.10 (t, J=7.5Hz, 3H).MS[M+Na]+=195.1.
Step 4:
The compound 4 of 80g is added in hydriding reactor, is added MeOH (800mL), addition chiral catalyst [Rh ((Sc,
Rp)-Duanphos)(NBD)]+BF4 -(equivalent: 0.1mol%), N2It replaces three times, H2Displacement is three times；It is stirred overnight at room temperature；Middle control
Raw material is complete, is concentrated to get crude product, and vacuum distillation obtains 60g colourless oil liquid, yield 75%, ee value 99.5%
(CHIRALPAK AD-H, 250 × 4.6mm, 5 μm, 1.0mL/min, 210nm, 25 DEG C, A: n-hexane, B: the second containing 1%TFA
Alcohol, A/B=95/5 (v/v)).
1H NMR(400MHz,CDCl3) δ 3.70 (s, 3H), 2.96-2.83 (m, 1H), 2.73 (dd, J=16.7,9.2Hz,
1H), 2.46 (dd, J=16.7,5.1Hz, 1H), 1.78-1.63 (m, 1H), 1.60-1.47 (m, 1H), 1.46-1.29 (m,
2H), 0.94 (t, J=7.3Hz, 3H).MS[M+H]+=175.0.
Step 5:
The compound 5 of 80g is added in the THF solvent of 800mL；Then the BH of 10mol/L is added dropwise3Me2S solution
(96mL, 2eq)；10 DEG C are stirred overnight；Fully reacting, water (200mL) quenching reaction, ethyl acetate (200mL) extraction, organic phase
Saline solution (200mL) washing, anhydrous sodium sulfate is dry, is concentrated to get crude product 72g, and yield 95.3% directly feeds intake in next step.
1H NMR(400MHz,CDCl3) δ 3.69 (s, 3H), 3.66 (dd, J=10.9,4.6Hz, 1H), 3.50 (dd, J=
10.9,6.8Hz, 1H), 2.39 (qd, J=15.4,6.6Hz, 2H), 2.12 (s, 1H), 2.07-1.98 (m, 1H), 1.46-1.31
(m,3H),1.29–1.17(m,1H),0.96–0.86(m,3H)。
Step 6:
The compound 6 of 90g is added in the THF solvent of 500mL, the 3N HCL aqueous solution of 500mL is subsequently added into；Room temperature
Stirring 2 hours；Raw material fully reacting, ethyl acetate (300mL) extraction, organic phase is washed with saturated salt solution (300mL), anhydrous
Sodium sulphate is dry, is concentrated to get crude product 72g, and vacuum distillation (90 DEG C of oil temperature, 0.5mmHg, 60-70 DEG C of fraction) obtains colorless oil
Product 50g, yield 70%, optical value+7.9 (c=1.289, ethyl alcohol), ee value 99.4% (GAMMA DEXTM 225,30m ×
0.25mm×0.25μm,1.0mL/min,200℃-250℃,CAN).Through (complete that medical sci-tech is limited purchased from Shanghai with standard items
Company) control after be confirmed as the product.
1H NMR(400MHz,CDCl3) δ 4.43 (dd, J=9.0,7.4Hz, 1H), 3.94 (dd, J=9.0,7.1Hz,
1H), 2.69-2.50 (m, 2H), 2.20 (dd, J=16.7,7.6Hz, 1H), 1.52-1.41 (m, 2H), 1.39-1.27 (m,
2H), 0.94 (t, J=7.2Hz, 3H).GCMS M=128.1.
Claims (10)
1. a kind of preparation method of compound 5, which is characterized in that it includes the following steps: in organic solvent, by compound 4
Catalytic hydrogenation as follows is carried out under the conditions of existing for the catalyst, obtains the compound 5；
The catalyst is [Rh ((Sc, Rp)-Duanphos) (X)]+Y-, wherein X is NBD or COD, Y BF4、PF6Or
SbF6；
R is methyl or ethyl；
2. the preparation method of compound 5 as described in claim 1, which is characterized in that the R is methyl；
And/or the catalyst is [Rh ((Sc, Rp)-Duanphos) (NBD)]+BF4 -；
And/or in the catalytic hydrogenation, the organic solvent is alcohols solvent, ether solvent, esters solvent and halogen
For one of hydrocarbon solvent or a variety of；The alcohols solvent such as methanol, the ether solvent such as tetrahydrofuran, institute
The halogenated hydrocarbon solvent stated such as methylene chloride；
And/or in the catalytic hydrogenation, the volume mass ratio of the organic solvent and the compound 4 is 5-
15mL/g, such as 10mL/g；
And/or in the catalytic hydrogenation, the molar ratio of the catalyst and the compound 4 is 0.0005:1-
0.5:1, such as 0.001:1-0.01:1；
And/or the reaction temperature of the catalytic hydrogenation is 10-50 DEG C, such as 15-25 DEG C.
3. the preparation method of compound 5 as described in claim 1, which is characterized in that still further comprise following steps: will change
Object 3 and R-OH are closed in SOCl2In the presence of carry out esterification as follows, obtain the compound 4；
4. the preparation method of compound 5 as claimed in claim 3, which is characterized in that in the esterification, the R-
OH is used as solvent and reactant simultaneously；
And/or in the esterification, the volume mass ratio of the R-OH and the compound 3 is 5-15mL/g, example
Such as 8-12mL/g, such as 10mL/g；
And/or in the esterification, the SOCl2Molar ratio with the compound 3 is 0.1:1-1:1, such as
0.35:1-0.45:1, such as 0.4:1；
And/or the reaction temperature of the esterification is 0-10 DEG C；
And/or the reaction time of the esterification is 2-3 hours.
5. a kind of preparation method of compound 6, which is characterized in that it includes the following steps:
(1) compound 5 is prepared according to the preparation method of compound 5 such as of any of claims 1-4；
(2) in organic solvent, by the compound 5 in BH3In the presence of carry out reduction reaction as follows, obtain institute
The compound 6 stated；
6. the preparation method of compound 6 as claimed in claim 5, which is characterized in that in the reduction reaction, described has
Solvent is the mixed solvent of tetrahydrofuran and dimethyl sulphide；In " mixed solvent of tetrahydrofuran and dimethyl sulphide ",
The volume ratio of the tetrahydrofuran and dimethyl sulphide can be 5:1-10:1, such as 8:1-9:1；
And/or in the reduction reaction, the volume mass ratio of the organic solvent and the compound 5 is 5-15mL/
G, such as 8-12mL/g；
And/or in the reduction reaction, the BH3Molar ratio with the compound 5 is 1.1:1-4:1, such as
1.8:1-2.5:1 such as 2:1-2.2:1；
And/or the reaction temperature of the reduction reaction is 5-30 DEG C, such as 5-15 DEG C, such as 10 DEG C.
7. a kind of preparation method of compound 7, which is characterized in that it includes the following steps:
(1) compound 6 is prepared according to the preparation method of compound 6 such as described in claim 5 or 6；
(2) in a solvent, the compound 6 is subjected in the presence of HCl cyclization as follows, obtained described
Compound 7；
8. the preparation method of compound 7 as claimed in claim 7, which is characterized in that in the cyclization, described is molten
Agent is the mixed solvent of tetrahydrofuran and water；In " mixed solvent of tetrahydrofuran and water ", the tetrahydrofuran and
The volume ratio of water can be 0.8:1-1.2:1, such as 1:1；
And/or in the cyclization, the volume mass ratio of the solvent and the compound 6 is 5-15mL/g, example
Such as 8-12mL/g；
And/or in the cyclization, the molar ratio of the HCl and the compound 6 is 2:1-3:1, such as 2.6:
1-2.7:1；
And/or the reaction temperature of the cyclization is 15-25 DEG C.
9. the preparation method of a kind of compound 4, compound 6 or compound 7, which is characterized in that the preparation side of the compound 7
Method includes the following steps: in a solvent, and compound 6 is carried out cyclization as follows in the presence of HCl, obtains described
Compound 7；R is methyl or ethyl；The condition of the cyclization is as described in claim 7 or 8；
The preparation method of the compound 6 includes the following steps: in organic solvent, by compound 5 in BH3In the presence of into
Row reduction reaction as follows, obtains the compound 6；R is methyl or ethyl；The condition of the reduction reaction
As described in claim 5 or 6；
The preparation method of the compound 4 includes the following steps: compound 3 and R-OH in SOCl2In the presence of carry out it is as follows
Shown in esterification, obtain the compound 4；R is methyl or ethyl；The condition of the esterification such as right
It is required that described in 3 or 4；
10. a kind of compound 6:
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