WO2014108011A1

WO2014108011A1 - Entecavir intermediates and preparation method thereof

Info

Publication number: WO2014108011A1
Application number: PCT/CN2013/089175
Authority: WO
Inventors: 刘念; 牟祥; 李倩
Original assignee: 重庆康施恩化工有限公司
Priority date: 2013-01-14
Filing date: 2013-12-12
Publication date: 2014-07-17
Also published as: CN103387587A; CN103387587B

Abstract

The present invention relates to important intermediate 2 of entecavir and a method for preparing entecavir intermediate compound 1 through ring-closing reaction of compound 2 under the condition of free radicals with transition metals as the center.

Description

Entecavir intermediate and preparation method thereof

The invention relates to a hepatitis B drug intermediate and a preparation method thereof, in particular to a key intermediate of entecavir, a methylene cyclopentane compound and a preparation method thereof.

Background technique

Entecavir, an antiviral (HBV) prescription drug, was first marketed in the United States in April 2005 by Bristol-Myers Squibb. The chemical name is: [IS- (1 α , 3 α , 4 § )]-2-yl-1,9-dihydro[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclo] ~611-嘌呤-6-one;

For the first report on its use as an antiviral drug, US526244; entecavir low-dose combination of drugs for the treatment of hepatitis B virus infection can be found in CN1310999 and CN1658844.

JOC 1985 (50) 755, CN1061972, WO9809964, CN1747959, etc. describe the preparation method thereof, the key is to synthesize the key intermediate cyclopentane compound, and the intermediate has the following problems. First, the preparation method is achiral cyclopentane. The olefin is the starting material, and the chiral group is constructed by using an expensive chiral ligand or chiral resolution, and the introduction of the chiral group is low in efficiency and high in cost.

Second, the yield in the next reaction with the guanine derivative was low, of which JOC 1985 (50) 755 reported a yield of only 27%.

Third, the position selection and chiral selectivity of the guanine ring are poor, and multiple stereoisomers are mixed after the anthracene ring, and it is difficult to prepare a high-purity product even by multiple column chromatography. For example, WO980996 reports that the ring-opening product is separated by multiple silica gel columns to give a purity of only 92%.

Fourth, the product after ring opening needs to be protected in the next reaction to protect the amino group on the guanine. The protection reaction is difficult, the product is unstable, and it is easily decomposed even on the silica gel column, and purification is difficult. Fifth, CN1747959 also reports the use of silane as a precursor of a hydroxyl group. After completing the basic structural synthesis of the target molecule, the conversion of the silane group to a hydroxyl group is accomplished using very severe oxidation conditions, so that the purity and yield are not high, and A special resin is required to separate.

Therefore, the direct use of this method for the preparation of entecavir is complicated, the yield is low, and the reaction conditions are harsh and unsuitable for industrial production.

Tetra edron 59 (2003) 9013-9018 reports a synthesis method for the synthesis of entecavir intermediate methylene cyclopentane. The core of the method is to open the epoxy through chlorotitanium titanate and combine with acetylene to obtain a ring-closing product. The ring closure yield is as high as 82%. However, this method has the following problems - First, it is necessary to use a highly toxic organotin to remove the 2-position hydroxyl group of glucose.

Second, when the cyclopentane intermediate is obtained, the 4-position hydroxyl group is inevitably removed when the 2-hydroxyl protecting group is removed, and the obtained product is separated by column chromatography.

Third, when reacting with guanine through Mitemo3⁄4u, nucleophilic attack can occur due to the positions of 9-N and 7-N. Although the 9-N selectivity is greater than 7-N, the reaction product of 7-N is unavoidable.

Therefore, this method is also not suitable for industrial production.

By combining the compound of formula 2 for the first time and then closing the important intermediate of entecavir shown in formula 1 under this condition, this method can effectively overcome the above disadvantages.

Summary of the invention

In the present invention, related terms are defined as follows:

The term "alkyl", alone or in combination with other groups, denotes a straight or branched monovalent glucone and a hydrocarbon group consisting of carbon and hydrogen atoms. "C1-6 alkyl" means a branched or straight-chain alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ft butyl , n-hexane.

"" refers to fluorine, chlorine, bromine and iodine.

"Haloalkyl" means an alkyl group as defined above substituted by one or more halogens, for example trifluoromethyl.

The term "alkoxy", alone or in combination with other groups, denotes a group R-0-, wherein R is alkyl as defined above. "C1-6 alkoxy" means a group R'-0-, wherein R' is a C1-6 fluorenyl group as captured above.

"Aryl" means a monocyclic or fused ring bicyclic aromatic ring containing a carbon atom. "C5-10 aryl" means an aryl group having 5 to 10 carbon atoms. For example, the C5-10 aryl group can be phenyl or naphthyl.

"Aralkyl" means an alkyl group as described above substituted with an aryl group as described above. "Acyl" refers to the group -CO-R, wherein R is alkyl, aryl, aralkyl as described above.

The aryl groups described above, whether as a group itself or as part of other groups such as an aryl fluorenyl group, an aryl fluorenyl group, may be optionally substituted with one or more substituents. When the aryl group is substituted, the substituent is preferably selected from the group consisting of C1-6 alkyl, Cl>6 alkoxy, halogen, aryl and nitro, more preferably selected from methoxy, ethoxy, Halogen, phenyl and nitro.

It is an object of the present invention to provide an intermediate of entecavir and a process for the preparation thereof.

The present invention provides new synthetic methods including -

1. Compound 2 and the transition metal trivalent German-centered radical ring-closing reaction to prepare the compound shown in Formula 1

among them:

PI and P3 may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxy-Wei group;

P2 is selected from the group consisting of C1-6 alkyl, haloalkyl, benzyl, t-BuMe ₂ Si, t-BuP3⁄4Si, Et ₃ Si, benzoyl, tetrapyran-2-yl, substituted with a phenyl ring Benzoyl, biphenyl "4-formyl"; the epoxy stereo configuration of the compound of Formula 2 may be in the R-configuration, the S-configuration or the 3⁄4S-configuration.

2, the preparation method of the compound 1 is prepared by the following method - preparing the compound of the formula 13 by double-base protection under Lewis acid catalysis,

Wherein: R1 is a hydrogen atom, a C1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group;

Under the conditions of the reaction, the compound of the formula 12 is obtained, P4 is an acyl group, and R1 is as defined above;

c The compound of formula 12 is selectively deprotected from a hydroxy protecting group under polar conditions in a polar protic solvent.

Where: Rl, P4 are defined as described above;

d. The compound of the formula 11 is obtained by the oxidation reaction and the elimination reaction in the polar preparation to obtain the formula 10

10

Where: R1 is defined as described above;

Reduction of the compound to give a compound of the formula 9,

I

Where: R1 is defined as described above;

Obtaining the ammonium of the compound of formula 8 under acidic conditions

Reacting with an amino protecting reagent under basic conditions to give a compound of formula 7

Where: Pl, P3 are defined as described above;

a compound of the formula 7 which gives a compound of the formula 6 in the presence of a hydroxyl activator,

Wherein: R2 is methylsulfonyl or p-toluenesulfonyl, and P1 and P3 are as defined above;

Closing the ring under basic conditions to give compound 5,

Where: PK P3 is defined as above;

Reduction to give a compound of formula 4,

Where: PI, P3 are defined as described above;

k. The compound of formula 4 is reacted with a Bestmann- Ohira reagent to give a compound of formula 3,

Where: Pl, P3 are defined as described above;

1. A compound of the formula 3 is reacted with a hydroxy protecting reagent to give a compound of the formula 1.

3. Another preparation method of compound 5 is as follows - a base protecting reagent is reacted to obtain a compound of formula 22,

Wherein: R1 is a C1-6 alkyl group, an aryl group, a substituted aryl group, and an aralkyl group;

b. a compound of formula 22 is reacted with a hydroxyl activating reagent to form a compound of formula 21,

Wherein: ^ is a 3⁄4-based activating group, and R1 is as defined above;

The compound is reacted with a halogenating reagent to prepare a compound of the formula 20,

20

Wherein: X is a halogen, preferably bromine; R1 is as defined above;

d. a compound of the formula 20 is reacted with acetyl aldehyde malonate in the presence of an alkaline reagent to give a compound of the formula 19,

AOHN COOEt

RiOCO 3⁄400Β 19

Where: R1 is defined as described above;

Decarboxylation to give the compound of formula 18;

11

f. The compound of formula 18 is resolved under L-ethylidene dilating enzyme, and the protecting group is further added to obtain the compound of formula 17,

ΡιΡ ₃

"COOH where: PI, P3 are defined as defined above;

Hydrogenation of the compound of formula 1 in the presence of a Lindlar catalyst,

Where: Pl, P3 are defined as defined above;

Closing the ring to obtain the compound of formula 15,

15

Wherein: X is a halogen, and P1 and P3 are defined as defined above;

i. The compound of formula 15 is ring-closed to give the compound of formula 5.

4. Compound 1 can also be prepared by the following method.

Reacting with an amino-protective detergent to give a compound of formula 33,

Where: P1 is defined as described above;

The compound is hydrolyzed by a Mitsunobu reaction to give a compound of the formula 32.

Hydroxy protection of the compound gives the compound of formula 31,

PI, P2 are defined as described above;

The compound is reacted with a carboxy protecting reagent to give a compound of the formula 30,

Where: RP P2 is defined as described above;

e. The compound of formula 30 is oxidized to give a compound of formula 29,

28

Where: Rl, PI, P2, as defined above;

f. Hydrolysis or alcoholysis of the compound of Formula 29 to give a compound of Formula 28,

28

Wherein: R2 is hydrogen, an organometallic ion such as sodium, a weight, a potassium ion, and a 'grac group, an aralkyl group, an substituted aralkyl group on the aromatic ring, and R1, P1, and Ρ2 are as defined above;

g. Reduction of the compound of formula 28 to give a compound of formula 27,

27

Where: Rl, Pl, P2, P3 are defined as above;

h. Compound of formula 27 is reacted with Wittig reagent to give compound of formula 26'

26

Where: Rl, PI, P2, P3 are defined as described above;

i. Reduction of the compound of formula 26 to give a compound of formula 25,

Where: Pl, P2, P3 are defined as described above;

j. The compound of formula 25 is reacted with a Bestmann-oMra reagent to give a compound of formula 24, OP ₂ NP ₃ P ₁

twenty four

Where: PI, P2, P3 are defined as described above;

k, the compound of the formula 24 is oxidized to give a compound of the formula 2.

.

6. a compound of formula 2,

Wherein: the epoxy stereo configuration can be R-configuration, S-configuration or R, S-configuration.

In order to better understand the present invention, the following detailed description of the present invention will be understood by the following examples. It should be understood that the following description is not intended to limit the scope of the invention. Various modifications and changes of the present invention are possible within the scope of the invention.

Example 1 (synthesis of compound 13a, m = I3⁄4)

13a

Under nitrogen protection, benzaldehyde (200g, 1887mmol, 8.3eq) was added to the 3000niL reaction flask, and anhydrous chlorination # (50g, 6.8mmol, l, 62eq) was added by electric stirring, and N-acetyl-D-gas-based glucose was added. 14a (50g, 226mmol, leq), 20-40Ό reaction for 18 hours, HPLC control, 14a less than 1%, stop the reaction, add 740g of ethyl acetate for 2 hours, filter, filter cake, a large amount of ethyl acetate wash, drum The wind was dried for 6 hours to obtain 11⁄2 white solid 60g, yield 86%.

Really inverted 2 (synthesis of compound 13a, Rl=Ph) Under nitrogen protection, benzaldehyde (200 g, 1887 mmol, 8.3 eq) was added to a 3000 mL reaction flask, and anhydrous p-toluenesulfonic acid monohydrate (0.45 g, 2,26 mmol, O.Oleq) was added by electric stirring, and N-acetyl was added. -D- Glucosamine Ma (50g, 226imnol, leq), After reacting with 204CTC for 18 hours, HPLC control, 14a less than 1%, stop the reaction, add 740g of ethyl acetate 65'C for 6 hours, filter, filter, a large amount of filter cake The mixture was washed with ethyl acetate, and pulverized for 6 hours to obtain a white solid of 55 g of a white solid, yield 78.6 «1⁄2.

Example 3 (synthesis of compound 1, Rl=Ph, P2=P4=Ac)

Add 13a (50g, 161.7mmol, leq), pyridine (680g, 8597mmol» 53eq) to a 1L reaction vial, add dropwise, add acetic anhydride (320g, 3134, 4mol, 19.4eq), control temperature 20-30 °C After the dropwise addition, the temperature is raised to 40-45 ° C for 10 hours, the HPLC control 13a is less than 1%, the controlled temperature is below 60 ° C, the solvent pyridine is distilled under reduced pressure, steamed to the system ffi, the distillation is stopped, and the temperature is lowered to 15-25 Ό. Add 340 _g of tert-ether ether, stir for 5 hours, filter, and blast dry to obtain 55.9 g of white solid 12a, yield 89%.

Example 4 (synthesis of compound 12b, l=P, P2=P4=PhCO)

Add 13a (50g, 161.7mmol» leq), pyridine (680g, 8597mmol» 53eq) to a 1L reaction flask, add benzoyl gas 226g, 1608mmol, 10eq), control temperature 20-3 (TC, drop) After the addition, the temperature is raised to 40-45 °C for 10 hours, the HPLC control 13a is less than 1%, the temperature is controlled below TC, the solvent pyridine is distilled under reduced pressure, steamed to a thick system, and the distillation is stopped to cool to 15-25 °C. 34 (3⁄4 methyl ether), stirred for 5 hours, filtered, blasted to dry 70 g of white solid 12b, yield 83.6%.

Example 5 (Synthesis of Compound 11a, Rl = Ph, P4 = Ac)

Add 112g of anhydrous methanol to the IL reaction bottle, and control the temperature to be lower than 3 (TC is used for 2 hours after ammonia gas is used; Under nitrogen protection, add 12a (55.9 g, 142.1mmol, leq) to a 1L reaction flask, add 400g of THF, start stirring and cool down to 40-45'C, start » ammonia solution in methanol, drip for about 1 hour, control After 6.5 hours of temperature reaction, the sample was continuously controlled until the intermediate conversion was complete, the temperature was controlled below 50 ° C, the solvent was concentrated, and 900 g of ethyl acetate was added for 2 hours, filtered, and the filter cake was washed with plenty of water, and the temperature was 70 ° C. Osmium, a white solid lla 39.8 g, yield 79.2%.

Really pour 6 (synthesis of compound lib, Ml=Ph, P4=PhCO) Add 112g of anhydrous methanol to the 1L reaction flask, control the temperature below 30'C for 2 hours, wait for use; under nitrogen protection, in 1L reaction Add 12b (55.9 g, 142.1mmol, leq) to the bottle, add 400g of THF, start the β mix and cool down to 40-45Ό, start to add ammonia solution in methanol, about 1 hour»Bi, control temperature 4045Ό reaction 6.5 hours after sampling Control until the intermediate-body transformation is complete, control the temperature below 50'C, start to concentrate the solvent, add 900g of ethyl acetate for 2 hours, filter, filter cake washed with plenty of water, blast at 70 ° C for 12 hours, white solid Ub 42.0g, yield 84.1%

Really inverted 7 (consideration of compound 10a, Rl=Ph)

Under nitrogen protection, add 1a (40 g, 113,8 mmol, leq) to a 1 L reaction flask, and add 281.5 g of dimethyl sulfoxide ₍ cooling to 20-25'C, and quickly add acetic anhydride (60.7 g, 59.46 mmol, 5,5 eq), 30 minutes 漓 add, control at this temperature for 16 hours, sample HPLC controlled to 11a less than 1%, the reaction solution was added to 500mL ice water, stirred for 1 hour, filtered, product 70'C The blast was dried for 10 hours to obtain 10 g of white body 30 g, and the yield was 91%.

Example 8 (Synthesis of Compound 10a, Rl=Ph)

Under nitrogen protection, add llb "40 g, 96.7mmol» leq), dimethyl sulfoxide 281.5g, and cool down to 20-25 1 in a 1L reaction flask, and quickly add acetic anhydride (60.7g, 594, 57mmol, 6, leq) ), after 30 minutes, the reaction was controlled at this temperature for 16 hours, and the HPLC was controlled to l ib less than 1%. The reaction droplets were added to 500 mL of ice water, stirred for 1 hour, filtered, and the product was 70 Torr. After drying for 10 hours, 10 g of a white solid of 25 g was obtained, yield 89%. Example 9 (synthesis of compound 9a, l = Ph)

«a ia

In a 1L hydrogenation tank, add 10a (30g, 103.7mmol»leq) crude product, add 600g of solvent methanol, open and start S mix, add 10«% palladium carbon 5.3g, replace nitrogen three times, helium gas replacement three times, often After 5 hours of pressure hydrogenation reaction, the sampled HPLC controlled 10a was less than 3%, the reaction was stopped, cooled to 15 ° C, filtered, and the filtrate was concentrated under reduced pressure until a large amount of solid was precipitated and then filtered, and the filter cake was dried to obtain a solid of 28 g of white solid. , yield 93%. Example W (synthesis of compound 9a, R1 = I3⁄4)

In a 1 L hydrogenation reactor, 10a (30g, 103.7mmol, leq) crude product was added, 600g of solvent methanol was added, and after stirring, 5.3g of 10% platinum carbon was added, 3 times of nitrogen substitution, three times of hydrogen replacement, atmospheric pressure hydrogenation reaction 5 After the hour, the sampled HPLC controlled 10a was less than 3%, the reaction was stopped, cooled to 15 ° C, filtered, and the filtrate was concentrated under reduced pressure until a large amount of solid was precipitated and then filtered, and the cake was dried to obtain a solid of 25 g of a white solid, yield 82.7%. . Really inverted 11 (synthesis of compound 8a, Acid = HCl)

Da la

In a 1L reaction flask, add 9a (50g, ] 71.6mmol, leq), add 50mL of IN hydrochloric acid, and heat up the reaction for 2, 5 hours, HPLC control 9a less than 1%, cool down to 10'C and add 2 X 250mL The methyl chloride was extracted, and the water layer was steamed to obtain an oil which was naturally cooled and solidified to give a white solid Bg (yield: 97%). Example 12 (synthesis of compound 7a, PI = H, P3 = Boc)

Add 8a (50g, 253mmol, leq), methanol 500mL, control temperature 10-15 °C, adjust the pH to 9 with triethylamine (305.7g, 303.5mmol, 1.2eq), maintain the temperature range Add (Boc) ₂ 0 (66,4g, 303.5mmol, 1.2eq), add, control temperature 20-25'C reaction for 14 hours, sample HPLC control 8a less than 3%, add 200g ethyl acetate extract, concentrate Crystallization to 100 mL yielded 60 g of a white crystalline solid '7a, yield 90%.

Really inverted 13 (synthesis of compound 7b, P1=H, P3=Cbz)

Add 8a (50g, 253ramol, leq), methanol 500mL, control temperature 10-15 °C, adjust the pH to 9 with triethylamine (305.7g, 303.5mmol, 1.2εφ, maintain the temperature in this temperature range) Benzyl chloroformate (51.8g, 303.65mmol, 1.2eq), after adding, control temperature 20-25'C reaction for 14 hours, sample HPLC controlled 8a less than 3%, add 200g acetic acid acetic acid extraction, and concentrate to WOmL crystal, 65 g of a white crystalline solid 7b was obtained in a yield of 87%.

Example 14 Synthesis of Compound 6a (R2=, P1=H, P3=Boc)

7a ia

7a (9.9g, 37,89mmol, leq) was added to a 250mL reaction flask, 78.5g of pyridine was stirred and dissolved, and the temperature was lowered to 0-5Ό, and a di-methane solution of p-toluenesulfonyl chloride was added dropwise (28.2g, 37.?7mmol, Leq), after 45 minutes, the addition was completed, and the reaction was maintained at this temperature range for 2.5 hours. The HPLC was controlled without 7a, added to 200 mL of ice water, separated, and the organic phase was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to a fraction. The external temperature was lower than that of 6 g of a colorless oil of 13 g, and the yield was 82%.

Synthesis of compound 6b (R2=Ms, P1=H, P3=Boc) In a 250 mL reaction flask, 7a (10 g, 37.8 mmol, leq) was added, 78.5 g of 3⁄4tidine was stirred and dissolved, and the temperature was lowered to 0-5 °C. Add methanesulfonyl chloride in dichloromethane (28.'2g, 37,77mmol, leq), after 45 minutes, add dropwise, maintain the reaction in this temperature range for 2.5 hours, sample HPLC without 7a, add 200mL ice water The liquid and organic phase anhydrous sulphuric acid building is dry, the solvent is concentrated under reduced pressure until no fraction, and the external temperature is low (6, TC, 6b colorless oil 10.2g, yield 88.7%. Synthesis of Compound Sa of Example 16 (P1=H, P3=Boc)

In a 250 mL reaction flask, 6a (10 g, 24 mmol, leq), 66 g of methanol, potassium carbonate (11.7 g, 61.37 mmol, 2.5 eq) was added. (The mixture was refluxed for 2 hours, and the material in the HPLC was free from 6a, filtered, and the filtrate was concentrated to give a solid. 4.8 g, solid was added to 25 mL of saturated brine, extracted with 2×50 mL of ethyl acetate and concentrated to give 3.8 g, and the solid was crystallized with 10 mL of ethyl acetate 5 g of white solid 5a, yield 85%

Example 17 Synthesis of Compound 5a (Pl=B P3=Boc)

In a 250 mL reaction flask, 6b (8.1g, 24mmol, leq), 66g of dichloromethane, 66g (5g, 89.2mmol, 3.0eq) was added (the temperature was refluxed for 2 hours, the HPLC controlled material was not 6b, filtered, and the filtrate was concentrated. The solid was reduced to 4.8 g, and the solid was added to 25 mL of EtOAc (EtOAc), EtOAc (EtOAc)

Synthesis of Compound 4a of Example 18 (P1=H, P3=Boc)

5a 4a

5o (1.3g, 5.34mmol, leq), 31g of THF were added to the lOOmL reaction flask, the gas gas protection was lowered to -78'C, and 25% diisobutylaluminum hydride (12.12g, ll, 96mmol) was started to be added dropwise. , 2.24eq), after adding dropwise, control the reaction at this temperature for 30 minutes, control in TLC, without 5a, add 20% sodium potassium tartrate solution (25g, 17.72mmol, 3.3eq), quench, add 30mL of tert-butyl ether and slowly heat up After stirring for 1 hour, the mixture was separated, and the aqueous phase was extracted once with a tertiary bond. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give product 4a as colorless oil. reaction.

Synthesis of compound 19a (P1=H, P3=Boc)

5a (13g, 53.44mmol, leq), 100g of methanol was added to a 5 () 0mL reaction flask, the temperature was lowered to 20-25 氮气 under nitrogen, and sodium borohydride (2g » 52.81mmol» l.Oeq) was started. control in The temperature was reacted for 30 minutes, controlled by TLC, without 5a, neutralized by adding 2N hydrochloric acid to pH 6-7, added with 150 mL of tert-ether ether, stirred for 1 hour, and then separated, and the aqueous phase was extracted once and then combined, and the saturated ftzR was added. Washing, anhydrous sulfuric acid collar dried, concentrated product 4a colorless oil llg, yield 84% directly used in the next step. Example 20 Synthesis of Compound 3a (P1 = H P3 = Boc)

Under nitrogen protection, add 4a C l, 48g _f 6.03 ol, leq) to the KKtniL reaction flask, and 11.8g methanol was cooled to 0-5 ° C. After adding potassium acid ( 1.66g, 12.03mmol, 2eq), add ( 1-diazo-2-oxopropyl)phosphonic acid (Bestmann-ohira reagent) (i.38g, ?.19mmol, 1.2eq), naturally heated to room temperature for 1 hour, HPL C controlled 4a small 亍3 %, filtered and concentrated, the oil was passed through a silica gel column to give a 3a colorless oil, 1.2 g, yield 82%, directly used for the sputum reaction.

Synthesis of Compound 2a of P21; P P1=H, P2=TBS, P3=Boc)

Add 3⁄4 (0.76g, 3,15mmol, leq) to a 100mL reaction flask, add 6 Jg of di-methane to dissolve, add imidazole (0.64g, 9.4mmol, 3eq), add slowly 3⁄4 plus t-butyl dimethyl Chlorosilane di-nethane methane sputum C2.95g, 6.3mmol, 2eq), 20-25 C reaction 8 hours, HPLC control 3a reaction is completed, cooling 10-15'C added 0.5N hydrochloric acid for 10 minutes, then The organic phase is washed with a saturated chlorinated solution, anhydrous anhydrous magnesium sulfate is dried, and concentrated to give a colorless oil of <RTIgt;</RTI>

Synthesis of real W 22 compound la (P1=H, P2=TBS, P3=Boc)

THF 26,7 g, titanium dichlorotitanium oxide (1.05 g, 4.22 mmol, 3 eq)» was replaced in a 100 mL reaction flask for 10 minutes, and zinc powder was added for 1 hour under nitrogen protection. The reaction temperature was 20-3 (TC). Add 2a (0.5g, l, 41mol, leq) to another lOOmL reaction flask, and replace with 13.4g of THF nitrogen for 10 minutes, then add the prepared chlorotitanium tetrachloride THF solution, add and maintain the temperature at 20 After 3 hours of -3CTC reaction, the mixture was controlled by HPLC. The reaction of starting material 2a was completed. After distilling off THF under reduced pressure, 50 mL of tert-butyl ether was added to cool to 10-15, 10% sulfuric acid was added, and after stirring for 20 minutes, the mixture was separated, and the lower layer was treated with 50 mL of methyl tertiary ether. after extraction once with saturated brine and the organic phases were washed with water added over anhydrous magnesium sulfate and concentrated to give a brown oil which was directly la silica gel column to give the product 0.45g, yield _{89% ¾ NMR CCDC1 3, MHz} :. 600): 6 =0.067-0.158

(ra, 6H), 0.874-0.940 (m, 9H,), 1.452 (s, 9H), 1,730-2.046 Cm, 2H), 2.544 (s, 1H), 3.215(s, 1H), 3,681-3.734(d , 2H), 4.201-4.234 Cm, 1H), 4.571-4.590

(ra, 1H), 4.61 (s, 1H), 5.056 (s, IH), 5.197 (s, 1H).

Example 23 Synthesis of compound la (P1 = H, P2 = TBS, P3 = Boc) In a 100 mL reaction flask was charged THF 26, 7 g, titanium dichlorotitanium oxide (1.05 g, 4.22 mmol, 3 eq) » Hydrogen displacement 10 After a minute, manganese powder was added under nitrogen for 1 hour, and the reaction temperature was 20-30'C. 2a (0.5g, 1.41mol, leq) was added to another 100mL reaction flask, and 13.4g of THF was replaced by nitrogen for 10 minutes. Then, the prepared chlorotitanium tetrachloride THF solution was added dropwise, and the temperature was maintained at 20-30. 'C reaction 3 hours, HPLC control, the raw material 2a reaction is completed, distilled off THF under reduced pressure, add 50mL of methyl tertiary ether to cool to 10-15 ° C, add 10%» acid, stir for 20 minutes, then separate the liquid, the lower layer After extracting 50 mL of methyl tertiary ether, the organic phase was combined with saturated brine and dried over anhydrous magnesium sulfate and evaporated.

¹ H MR (CD 3⁄4, MHz; 600): δ = 0.067-0.158 (m, 6H), 0,874-0.940 (m, 9H,), 1.452 (s, 9H), 1.730-2.046(m, 2H)» 2.544 (s» lH)» 3.215(s, IH), 3.681-3.734(d, 2H), 4.201-4,234 (m, IH), 4.571-4.590 Cm, 1H), 4,61(s, IH), 5,056 ( s, 1H), 5.197(s, 1H). Example 24 Synthesis of Compound lb <Pl= Boc, P2=TBS, P3=Boc)

In a reaction flask of 5 () 0iTiL, THF 100 g, titanium dichloride (8.3 g, 33.34 mmol, 3 eq) was added, and after nitrogen substitution for 10 minutes, zinc powder was added under nitrogen for 1 hour, and the reaction temperature was 20-3 ( TC. Add 2b (3⁄4 10.97 1 leq) to another 500mL reaction flask, after replacing 100g of THF with nitrogen for 10 minutes, *add the prepared chlorotitanium tetrachloride THF solution, add it, keep the temperature at 20-30'C After 3 hours of reaction, the mixture was controlled by HPLC. After the reaction of the starting material 2b was completed, the THF was evaporated under reduced pressure. Then, 200 mL of tert-butyl ether was added to cool down to 10-15 Torr, 10% 3⁄4 acid was added, and the mixture was stirred for 20 minutes, and then separated, and the lower layer was used for 2 (K). After the extraction of the nL methyl tertiary ether, the organic phase was combined with saturated brine and washed with anhydrous magnesium sulfate, and then evaporated to give a brown oil, which was directly passed through a silica gel column to obtain a product of 4.0 g, yield of 79.65%.

_3⁄4 NMR (CDC1 ₃ , MHz: 600): 6 = 0.067-0, 158 Cm, 6H), 0.874-0.940 (m, 9H,), 1,452 (s, leg), 1,730-2.046 (m, 2H), 2,544 (s , ffl), 3.215(s»ffl), 3.681-3.734(d, 2H), 4.201-4.234 (m, 1H), 4.571-4.590 (m, 1H), 4.61(s, 1H), 5.056(s _f IH ), 5, 197(s, IH) „

= Boc, P2=TBS, P3=Boc)

In a 500 mL reaction flask, THF 100 g, titanium dichloride (8.3 g, 33, 34 mmol, 3 eq) was added, and after nitrogen substitution for 10 minutes, zinc powder was added under nitrogen for 1 hour, and the reaction temperature was 20-3 (TC). Add 2c (5g, 10.97mol»Icq) to another 500mL reaction flask. After 10 minutes of nitrogen replacement with lOOgTHF, add the prepared chlorotitanium tetrachloride THF solution and add it to maintain the temperature at 20-3 ( After TC reaction for 3 hours, HPLC was controlled. The reaction of starting material 2b was completed. After distilling off THF under reduced pressure, 200 mL of tert-butyl ether was added to cool down to 10-15 Torr, 10% sulfuric acid was added, and the mixture was stirred for 20 minutes, then separated, and the lower layer was used for 2 (K). After extracting once with mL of methyl sulphate, the organic phase was combined with saturated brine and washed with anhydrous magnesium sulfate, and then reduced to brown oil, and directly passed through silica gel column to obtain 4.2 g of ib product, yield 84%.

^! HM (CDC1 ₃ » MHz: 600): δ =0.067-0.158 (m» 6Η), 0.874-0.940(m, 9H,), 1.452 (s, 18H) , 1.730-2,046 Cm, 2H)» 2,544 (s , 1H), 3.215(s, 1H), 3.681-3,734(d, 2H)» 4.201-4,234 (ra, IH), 4.571-4,590 Cm, 1H), 4,61(s, IH), 5.056 (s, 1H), 5.197 (s, 1H).

Example 26 Synthesis of Compound lb (Pl = H» P2 = TBS » P3 = Boc)

^M 1 a

In a 100 mL reaction flask, 26.7 g of THF, titanium dichloride (1.05 g, 4.22 mmol, 3 eq) was added, and after nitrogen substitution for 10 minutes, zinc powder was added under nitrogen for 1 hour, and the reaction temperature was 20-3 (TC). After adding 2d (0.5g, 1.41mol, leq) to another lOOmL reaction bottle and replacing it with 13.4g of THF nitrogen for 10 minutes, the prepared chlorotitanium tetrachloride THF solution was added dropwise, and the temperature was maintained at 20- 30'C reaction 3 hours, HPLC control, the raw material 2a reaction is completed, after distilling off the THF, add 50mL of methyl sulphate to cool to 10-15 °C, add 10% sulphate, stir for 20 minutes, then dispense. The lower layer was extracted once with 50 raL of thymidine, and the organic phase was combined with saturated brine. The dried magnesium sulfate was dried and concentrated to give a brown oil, which was directly passed through a silica gel column to obtain a product of 0.44 g, yield 87% _3⁄4 MR (CDC1 ₃ , MHz: 600): 6 =0.067-0.158

Cm, 6H) , 0.874-0,940(m, 9H,) _f 1.452 (s, 9H) , 1.730-2.046 (m, 2H), 2,544 (s, 1H), 3.215(s, 1H), 3.681-3.734(d , 2H), 4.201-4.234 (m, 1H) , 4.571-4.590

(m» 1H), 4.61 (s, 1H), 5.056 (s, 1H), 5, 197 (s, 1H).

Example 27 Synthesis of Compound 22a (Rl=Ph)

^H °-\ ― _ ^ drying,

23i 22a

Add 5a C 500g, 5.81 1, leq) to a 5L anti-bottle with nitrogen to add 1L of pyridine (4«g, 5.81mol, leq), cool down to 5Ό, add benzoyl chloride (736 g, 5.25) Methyl, 0.9 eq) dissolved in 1 L of dichloromethane solution, maintained at a temperature below 10 ° C for 3 hours, the reaction compound was naturally warmed to room temperature for 12 hours, TLC controlled benzoyl chloride was completely reacted, and 1 M sulfuric acid (3 X 600 mL) was added. And 2 X 600 mL of water, the organic phase was concentrated to 900 mL, and then 750 mL of ethanol was added to cool and precipitate crystals, which were filtered, and the filtrate was concentrated to obtain 519 g of orange-red oil 22a, yield 52%. Example 28 Synthesis of Compound 21a (M = Ph R2 = Ms)

Under a nitrogen atmosphere, 21a (278 g, 1.46 mol leq), 2.1 L of dichloromethane were added to a 5 L reaction flask, cooled to 0 C, triethylamine (224 mL, 1.61 mol, 1.1 eq) was added, and 4-methylnitrobenzene was added. Base) 1 pyridine (4.45 g, 36 mmol, 0.025 eq), dropwise addition of methanesulfonyl gas (125 mL 1.61 mol. 1,1 eq) in 100 mL of dichloromethane, maintaining the temperature below 5 Ό, 3⁄4 After completion, the temperature was maintained at O'C for 2 hours, and there was no 21a in the HPLC. After adding 1.5L of water, the mixture was mixed for 5 minutes, and then separated. The layer was saturated with 1.5 L of saturated sodium hydrogencarbonate solution and 1 M of hydrochloric acid with 1.5 L of strip. Anhydrous magnesium sulfate was concentrated and concentrated to obtain a brown oil of 21 g (yield: 90%).

The synthesis of compound 20a (Rl=Ph, X=Br)

Under nitrogen protection, 21a (345 g, 1.29mol, leq) was added to a 3L reaction flask, 1.7L of acetone was added, and the temperature was lowered to 10'C. The temperature was lower than 15'C and lithium bromide was added (223 g 2.57 1, 2.0 eq). After the addition, the reaction was maintained at this temperature for 1.5 hours, and the TLC was controlled without 2 la. After filtration, the filtrate was concentrated under reduced pressure, and then 2L ethyl acetate was added, and the mixture was washed with anhydrous magnesium sulfate and filtered to afford 303 g of 20a brown oil. Yield 0% ₀

Example 30 Synthesis of Compound 19a (Rl=3⁄4)

Ethyl diethylaminoethyl malonate (258 g l. Wmol, leq), 3 L of tetrahydrofuran, potassium tert-butoxide (146 g, 1.30 mol, 1.09 eq), refluxed for 1 hour, and added 5 (M) mL of tetrahydrogen The 19a (300 g, l, 19 mol, l eq) dissolved in the sputum was added for 10 minutes, refluxed for 2.5 hours, and the remaining 20% of TLC was still added, supplemented with diethyl acetamidomalonate (100 g 0.47 mol, 0.39eq) and butanol C58g, 0.417mol, 0.39eq), after refluxing for 10 hours, no T2 in TLC, cooled to room temperature, filtered, concentrated under reduced pressure to 1L, then added 2L ethyl acetate, 0.1N 1 L of hydrochloric acid was washed, washed with 1 L of water, and the organic phase was concentrated to give 365 g of a brown oil (yield: 79%).

Example 31 Synthesis of Compound 18a

In a 5L reaction flask, 13⁄4 (300 g, 0.77 mol, leq), 1.5 L of ethanol, 1.5 g of water, sodium hydroxide (C22.5 g, 2.31 1, 3 eq) were heated and refluxed for 4 hours, and there was no residual hydrazine in the TLC. Concentrate the ethanol, concentrate 1 L of ethyl acetate, adjust the pH to 3.5 with concentrated hydrochloric acid, heat to reflux for 24 hours, cool, dilute the salt to H to 2.5, add 1.5 L of ethyl acetate, and use 45% sodium sulphate in the aqueous phase. Adjust pH to 6.0, concentrate under reduced pressure, add residue to 500 mL of methanol, filter, add 25 g of activated carbon, heat up 50 Torr, stir for 20 minutes, filter, and concentrate the filtrate under reduced pressure to give 18a orange & color oil 149g yield 100%. Synthesis of 13⁄4 (P1=H, P3=Boc)

Add 18a (125g, 0.67mol, leq), 30Mm KH ₂ PO ₄ 1.7L H7 to the 5L reaction flask, add L-ethylidene (200U/g substrate) to room temperature to 6 (TC maintain PH7 reaction until ^- NMR control showed a conversion rate of more than 40%, cooled to 20-25 C, added Boc ₂ 0 (47 g, 0.27 mol, 0.4 eq) dissolved in 200 mL of tetrasfuran solution, 20-25'C reaction, maintaining the reaction pH 10 Until the constant, add 5 () 0mL of tert-butyl ether, add potassium hydrogen sulfate to adjust the pH to 3, add ethyl acetate 3 X 1L extraction, organic phase combined, no The water sulfuric acid was dried and filtered, and the steam was obtained to obtain 44 g of a yellow oil 17a' yield of 36%.

=H, P3=B

Add 17a (30g, 0.162mol, leq) to a 2L hydrogenation reactor, add 3g of Lindlar catalyst, replace it with nitrogen for 3 times, hydrogenate to lbar, temperature 20' HPLC control 17a less than 1%, nitrogen replacement after pressure relief Filtered and concentrated to give 30 g of 16a oil.

Add 16a (30 g, 0.162 mol, 1 eq), 300 mL of chlorohydrofuran, and add N-bromosuccinimide (31.71 g, 0.178 mol, Ueq) at a temperature of 20-25 °C in a 1 L reaction flask. The reaction was carried out for 30 minutes, and the mixture was controlled under HPLC for 16a. The solvent was concentrated under reduced pressure, and then ethyl acetate (100 mL) and 120 mL of hexanes were added for 30 minutes, and the product 15a was obtained as a white solid.

Synthesis of compound 35a (P1=H, P3=Boc)

15a (29 g, 0.0895 mol, 1.0 eq), 290 mL of methanol, potassium carbonate (42.6 g, 0.223 mol, 2.5 eq) was refluxed for 2 hours in a 500 mL reaction flask, 15a was filtered in HPLC, filtered, and the filtrate was concentrated to give 20 g. White solid 5a, yield 92%.

Example 36 (Synthesis of Compound 33a, Pl = Boc)

Add L-hydroxyproline (60g, 457mmol, leq), tetrahydrofuran 600mL, water 300mL in a 2L reaction flask, cool down to 25-30'C, add 10% sodium oxide 180mL, add (Boc) ₂ 0 (135.8g, 622mmol, 1.36eq) was added, after maintaining the reaction at this temperature for 12 hours, the HPLC was controlled without L-hydroxyproline 10% potassium sulfate solution to adjust the pH to 2.0-2.5, 2 X250mL acetic acid The ester was extracted twice and concentrated to give 97.8 g of a colorless oil (yield: 92.43%).

Really inverted 37 (synthesis of compound 32a, Pl=Boc)

Under a nitrogen atmosphere, 33a (94.2g, 407.35mmol, leq), 1250g THF was added to a 2L reaction flask, triphenylphosphine C320g, 1222mmol, 3.0eq) was added, and the temperature was reduced to 0-5 °C and azodicarboxylic acid was added dropwise. Isopropyl ester (240g, llSOmmol, 2.9eq) 1 hour drop, control temperature 25- 30 ° C reaction for 3 hours, HPLC control no raw material left 33⁄4, add sodium bicarbonate solution (501.45g, 895.62mmol, 2.2 Eq) At the end of the dropwise addition, the reaction was carried out at room temperature for 8 hours. There was no residual intermediate in the HPLC. After decomposing the latent agent under reduced pressure to THF-free, a large amount of solid was precipitated, filtered, and the filter cake was washed with 2×250 mL of water, and the aqueous phase was combined. The glacial acetic acid was adjusted to a ratio of 2.0 to 2.5, extracted with 2 X 500 mL of acetic acid, and concentrated to obtain 63.23 g of compound 32a in a yield of 67.1%, which was directly used for the sputum reaction.

Example 38 (combination of compound 3⁄4 31a, Pl=Boc, P2=TBS)

32a 31a In a 2L reaction flask, add 32a (36.30g, 157mmol, leq), imidazole (53.43g, 785mmol, 4.1⁄2q) dichloromethane 266g, cool down to 10-15'C, add t-butyldimethylchlorosilane dropwise Dichloromethane solution

(135g, l?3mmol, Ueq), after 3 hours of addition, naturally warmed to 20-25 'C, after 10 hours of reaction, HPLC controlled, no 13⁄4 no residue, 0.5N ip acid added to adjust pH to 2-2.5 The liquid was separated, washed with hydrazine and sodium chloride solution, and steamed to obtain 54 g of oil as a 31a, W 99%, which was directly used for the next step.

, Rl=t-Bu)

31a 30a

In a 500 mL reaction flask, add 31⁄4 (58.8§,345.511111101,1€9), 4-dimethylaminopyridine (4.16§, 34.0, 0.2eq), 148g t-butanol to 10-15 °C, drop (Boc ₂ 0 of the West Gas Furan solution (225.8g, 425.43ramol, 2.5eq), after 3 hours, the temperature is raised to 20-25Ό, 12 hours after the reaction, the HPLC control 12a is less than 2%, and the t-butanol is distilled off under reduced pressure. After tetrahydrofuran, it was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated.

t-Bu)

30a (68.3g, 170.07 iol, leq), 1000g of ethyl acetate, 230g of purified water in a 2L reaction flask under nitrogen, cooled to 0 ° C, added RuCl ₃ .3⁄40 (10.8g, 41,3mmol, 0.24eq ), adding sodium periodate solution (663⁄4, 1550mmol, 9. leq), after 3 hours of dropwise addition, maintaining the reaction at 0-5 ° C for 8 hours, HPLC controlled 30a less than 3%, liquid separation, aqueous phase After taking 250 mL of the methyl sulphate, the organic phase was combined, washed with 2×250 mL of brine, dried over anhydrous magnesium sulfate

Example 41 (Synthesis of Compound 28a, Pl=Boc» P2=TBS» Rl=t-Bu» R2=Me)

Add 29a (30g, 72.18mmol, leq) to a 1L reaction flask, add 300g of methanol, cool to O'C, add 25% sodium methoxide solution (60g, 277.8mmol, 3.84 eq), add, and maintain The temperature was reacted for 2-3 hours, and the HPLC was controlled without 2, 0.5N potassium hydrogen sulfate solution was adjusted to pH between 6 and 7. After concentration of methanol, ethyl acetate was extracted, dried, and concentrated to obtain 30 g of white solid a. 92.8%.

Example 42 (Synthesis of Compound 28a, Pl = Boc, P2 = TBS, Rl = t-Bu, R2 = Li). In a 1 L reaction flask, 29a (30 g, 72.18 mmol» leq) was added, 300 g of tetrahydrofuran was added, and the temperature was lowered to 0. °C, add lithium oxide (11.6g, 277.8mmol, 3.84 eq), add and maintain at this temperature for 2-3 hours, HPLC control without 29a, 0.5N potassium hydrogen sulfate solution to adjust the pH to 6- After concentrating between methanol, ethyl acetate was extracted, dried, and concentrated to give 28 g of white solid 28a, yield 85%.

Example 43 (Synthesis of Compound 27a, Pl = Boc, P2 = TBS, P3 = H, Rl = t-Bu, R2 = Me)

Add 28 a (30 g»67minol, leq) to a 1L reaction flask, 300 mL of THF, cool to -78, add 25% diisobutylaluminum hydride (38 g, 6 mmol, 1.0 eq) dropwise. The reaction was maintained at this temperature for 30 minutes. There was no residue in HPLC control 28a. It was quenched by adding 10% sodium potassium tartrate. The mixture was naturally warmed to 20 ° C for 1 hour, and the mixture was separated. The organic phase was washed twice with saturated brine. The water magnesium sulfate was dried to obtain 27 g of a colorless oil (yield: 82%).

Example 44 (Synthesis of Compound 26a, Pl = Boc, P2 = TBS, P3 = H, M = t-Bu)

27* ^Aa

Under a nitrogen atmosphere, potassium tert-butoxide (7 g, 62.9 mmol, 1.61 eq) was added to a 500 mL reaction flask, and anhydrous 100 mL of tetrahydrofuran was added to cool to 5-10 ° C, and methyltriphenyl bromide (23.6 g was added). , 66.0mmol» 1.69eq), naturally warmed to room temperature for 1 hour, cooled to O-5'C, added 27a tetrahydrofuran solution (70 g, 54.8 mmol, 1.0 eq) to maintain the reaction at this temperature for 1 hour, HPLC control No 27a, filtered, the filtrate was concentrated, dissolved in 100 mL of tert-butyl ether, cooled to 10-15 ° C, pH adjusted to 0-2 with 0.5 acetic acid, separated, washed twice with saturated organic sodium chloride, anhydrous magnesium sulfate After drying, it was concentrated by filtration to obtain 15.4 g of a 26a oil, yield 94.9%.

Really pour 45 (synthesis of compound 26a, Pl = Boc, P2 = TBS, P3 = H, Rl = t-Bu). Under a nitrogen atmosphere, sodium hydride (1.51 g»62.9 mmol»1.61 eq) was added to a 500 mL reaction flask. Add anhydrous 100 mL of tetrahydrofuran to 5-1 CTC, add methyltriphenyl bromide β (23.6 g, 66.0 mmol» 1.69 eq), naturally warm to room temperature for 1 hour, cool to 0-5 Torr, add 27a tetrahydrofuran solution ( 70 g, 54.8 mmol, l.Oeq) maintained at this temperature for 1 hour, HPLC controlled without 27a, filtered, concentrated filtrate, dissolved in 100 mL of tert-butyl ether, released to 10-15 Ό, 0.5 acetic acid adjusted to pH 0 The mixture was washed twice with saturated sodium chloride and dried over anhydrous magnesium sulfate.

Really invert 46 (combination of compound 26a, Pl=Boc, P2=TBS» P3=H)

2«a 28a

In a 1 L reaction flask, add 26a (22g, 52.9mmol, leq), 530g of tetrahydrofuran, and cool down to -78Ό ' 25% diisobutylaluminum hydride (60.4g, 106.2mmol, 2,0eq), add, control The temperature Sft was reacted at -78 ° C for 30 minutes, controlled by HPLC, without 26a, after quenching with anhydrous methanol, adding 10% potassium uranium tartrate 200g, gradually warming to room temperature, stirring for 1 hour, liquid separation, organic phase saturated gasification sodium washing The mixture was dried twice with anhydrous magnesium sulfate, filtered and evaporated to ethylamine. Example 47 (Synthesis of Compound 24a, Pl=Boc, P2=TBS, P3=H)

25a 24a

Add 25a (13.4g, 39mmol, leq) to a 500mL reaction flask, 158g of anhydrous methanol, cool down to 5 'C, add anhydrous potassium carbonate (10.7g, 77.5mmol, 2eq), add (1-heavy gas base) -2-Oxopropyl). Lintami (Osmami- oMra reagent) (9.1g, 46,9mmol, 1.2eq), added dropwise, naturally heated to 20-25 ° C reaction 1 hour 吋 101 ^ control 3⁄4 Less than 5%, filtered, filtrate * reduced to 24 g oil 12.5 g, yield 94%,

Example 48 Synthesis of Compound 2a, Pl = Boc, P2 = TBS, P3 = H)

3a 2a

Under nitrogen protection, add m-chloroperoxybenzoic acid (4.8g, 29.6mmol, leq) to the reaction flask of WOmL, and dichloromethane 53g temperature 20-25 'C, stir and dissolve, then add 2a (10g, 29,5) The mmol, leq) system has no obvious temperature rise. After maintaining the temperature in this temperature range for 52 hours, there is no 2a in the TLC control, the saturated acid chloride is washed with uranium, the saturated sodium chloride is washed, the magnesium sulfate is dried, and the product is obtained as a colorless oil. 10 g, yield 95.5%, used directly in the sputum reaction. 3⁄4 NMR CCDCta, MHz: 600): δ = 0.071-0.179 (m, 6Η), 0.874-0.940 (111, 9H)» 1.443-1.482 Cm, 9H), 1.786-1.997 (m, 2H), 2.281-2.292 ( t, 1H), 2,561-2.974(1X1' 3H), 3.649-3.828(d, 1H), 4.575 (s, 1H), 5,294-5.473(d, 1H)

Claims

A method for preparing a compound represented by 1. It is characterized in that:

The compound represented by Formula 2 is used as a raw material, and is prepared by ring-closing under the free radical condition of the transition metal ^ 3 center, wherein:

PI and P3 may be the same or different and each represent a hydrogen, an alkoxycarbonyl group or an aralkoxy group;

P2 is selected from C1-6 alkyl, haloalkyl, _{base, t- BuMe 2 Si, t-} BuPh 2 Si, Et 3 Si, benzoyloxy, tetrahydropyran-2-yl, substituted on the phenyl ring with The benzoyl group and the biphenyl-4-formyl group; the epoxy stereo configuration of the compound of Formula 2 may be in the R-configuration, the S-configuration or the R, S-configuration.

The process according to claim 1, wherein the radical in which the transition metal is centered is a radical centered on trivalent titanium.

3. A process for the preparation of a compound 2 according to claim 1, characterized in that:

Preparation of a compound of formula 13 by double-path base protection catalyzed by Lewis acid,

Wherein: R1 is a hydrogen atom, a C1-6 fluorenyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group;

The reaction is carried out under the conditions to obtain the compound of the formula 12,

Wherein: P4 is an acyl group, and R1 is as defined above;

Preparation of the compound of formula 12 under selective conditions, selective removal of the hydroxy protecting group P4 from the polar protic solvent

Where: Rl, P4 are defined as described above;

The compound of the formula 11 is subjected to an oxidation reaction and a elimination reaction in a polar solvent to obtain a compound of the formula 10,

10

Where: R1 is defined as described above;

The compound of formula 9 is obtained,

8

Where: R1 is defined as described above;

Obtaining the ammonium salt of the compound of formula 8 under the conditions of the reaction,

Reaction with an amino protecting reagent under conditions to obtain a compound of formula 7,

Where: Pl, P3 are as defined above;

a compound of formula 6 is obtained in the presence of a base activator,

Wherein: R2 is a methylsulfonyl group, a p-toluenesulfonic acid group, and P1 and Ρ3 are as defined above;

The compound of formula 6 is ring-closed under basic conditions to give compound 5,

Where: Pl, P3 are defined as described above;

Originally obtained a compound of the formula 4,

Where: PI, P3 are defined as described above;

The Bestmaim-Ohira reagent reacts to give a compound of formula 3,

Where: PI, P3 are defined as described above;

The compound of the formula 3 is reacted with a hydroxy protecting reagent to give a compound of the formula 2.

4. The compound of formula 3, wherein the compound of formula 5 is prepared as follows:

Reagent reaction to give a compound of formula 22,

twenty two

Wherein: R1 is a C1- 6 graft group, an aryl group, a substituted aryl group, and an aryl fluorenyl group;

Reagent reaction to form a compound of formula 21,

Wherein: R2 is a hydroxyl activating group, and R1 is as defined above;

Preparing a compound of formula 20 by reacting with a reagent,

20

Wherein: X is a halogen, preferably bromine; R1 is as defined above; The compound of formula 20 is reacted with diethyl acetylaminomalonate in the presence of an alkaline reagent to give a compound of formula 19,

AcHN COOB 19

Where: R1 is defined as described above;

The compound of formula 19 is decarboxylated by alcohol to give a compound of formula 18;

^- NHAc

COOH

i l

The compound of the formula 18 is resolved under the conditions of L-acetylase, and the protecting group is further added to obtain a compound of the formula:

HO-^

17

Where: PI, P3 are defined as defined above;

Adding S to the compound of formula 16 in the presence of a lar catalyst,

16

Where: Pl, P3 are defined as defined above;

To the compound of formula 15,

15

Wherein: X is a halogen, and P1 and P3 are defined as defined above;

The compound of the formula 15 is ring-closed to give a compound of the formula 5.

A process for the preparation of a compound 2 as shown in claim 1, which is characterized in that _:

L-proline is reacted with an amino protecting reagent to give a compound of formula 33,

33

Where: PI is as defined above;

The compound of the formula 33 is hydrolyzed by the Mtsunobu reaction to obtain the compound H represented by the formula 32;

32

Compound group represented by formula 32 is protected to give a compound of formula 31,

Where: Pl, P2 are defined as described above;

The carboxy protecting reagent is reacted to obtain a compound of the formula 30,

30

Where: Rl, Pi, P2 are defined as described above;

The compound of formula 30 is oxidized to give a compound of formula 29,

P,

29

Where: Rl, PI, P2, as defined above;

Hydrolysis or alcoholysis of the compound of Formula 29 to give a compound of Formula 28,

OP ₂ NP, P ₃

26 Wherein: R2 is hydrogen, an organic metal ion such as sodium, lithium, potassium ion, and an alkyl group, an aralkyl group, an substituted aralkyl group on the aromatic ring, and R1, P1, and P2 are as defined above;

Originally obtained a compound of the formula 27,

27

Where: Rl, Pi, P2, P3 are defined as described above;

Wittig reagent reaction gives the compound of formula 26,

Where: Rl, Pl, P2, P3 are defined as above;

Reduction of the compound of Formula 26 to give a compound of Formula 25,

Wherein: Pl, P2, P3 are as defined above; the compound of formula 25 is reacted with BestmamwiMra to give a compound of formula 24,

0P ₂ ΝΡ ₃ Ρ,

twenty four

Where: ΡΚ Ρ 2, Ρ 3 are defined as described above;

The compound of the formula 24 is oxidized to give a compound of the formula 2.

6. A compound of formula 1.

2