CN109456212A - Synthetic method of the one seed sand library than bent intermediate - Google Patents
Synthetic method of the one seed sand library than bent intermediate Download PDFInfo
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- CN109456212A CN109456212A CN201811463256.0A CN201811463256A CN109456212A CN 109456212 A CN109456212 A CN 109456212A CN 201811463256 A CN201811463256 A CN 201811463256A CN 109456212 A CN109456212 A CN 109456212A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
Synthetic method the present invention relates to a seed sand library than bent intermediate.Mainly solve the not high technical problem of expensive reagents existing for existing synthetic method, severe reaction conditions, yield.Synthesis step of the present invention includes: that (1) N-Boc-D-4,4 '-biphenylalanine and Michaelis acid are condensed to yield compound 1 under condensing agent effect;(2) compound 1 is restored to obtain compound 2 with reducing agent;(3) compound 2 is dissolved in organic solvent, under the action of inorganic metal alkali and iodomethane obtains compound 3;(4) compound 3 heats decarboxylation in toluene solution and contracting ring obtains compound 4;(5) isomerization of the compound 4 under organic metal alkali effect obtains compound 5;(6) open loop under the action of inorganic metal alkali of compound 5 obtains compound 6;(7) compound 6 is catalyzed to obtain final product in ethanol by acidic catalyst.
Description
Technical field
The invention belongs to the preparation technical fields of organic synthesis route and its bulk pharmaceutical chemicals intermediate, in particular to a seed sand library ratio
The synthetic method of bent intermediate.
Background technique
According to statistics, whole world heart failure patient about 1.17 hundred million at present, wherein there are about 30,000,000 in China.Cardiotonic agents
Entresto is eutectic drug of the Sha Ku than song (Sacubitril) and Valsartan, it is considered to be past 10 years Heart disease neck
One of the maximum progress that domain obtains.
The entitled 4- of Sha Ku ratio Qu Huaxue { [(2S, 4R)-(1,1 '-biphenyl -4- base) -5- ethyoxyl -4- methyl -5- oxo -
2- amyl] amino } -4- Oxoacetic Acid, structure is as follows:
Synthesis at present synthesizes husky library than that will use key intermediate (compound number: A): (2R, 4S) -4- ammonia in bent route
Base -5- (1,1 '-biphenyl -4- base) -2 methyl valeric acid ethyl ester
Sha Ku than in bent intermediate A containing containing two chiralitys, maximum synthesis difficult point be how with economy, efficient method come
It constructs skeleton and introduces two chiral centres.
Early in disclosing the compound and preparation method thereof in 1992, United States Patent (USP) US5217996, this process employs
Palladium chtalyst couples, ties up terraced west reaction and chiral catalysis reduction, and the route of higher cost, synthesis is as follows:
Novartis in 2014 and nine divisions of China in remote antiquity medicine company, which are combined, has declared patent WO2014032627, and the grignard of chiral epichlorohydrin is utilized
Reaction, light are prolonged reaction (Mitsunobo reaction) and chiral catalysis and are restored, and severe reaction conditions are not easy to amplify, synthesize
Route it is as follows:
2016 Nian Hongyuan medicine companies have declared patent CN105924355, although only three-step reaction, secondary used is difficult to amplify
The thunder husband maschi (Reformasky) of production is reacted and special enzyme' s catalysis, does not have economic value, the route of synthesis
It is as follows:
There are also people to this later studies have reported that.But it is not high all to there is overall yield of reaction, and severe reaction conditions add hydrogen to select
The problems such as property is bad, and agents useful for same is expensive.
Summary of the invention
Synthetic method the purpose of the present invention is to provide a seed sand library than bent intermediate, mainly solves existing synthetic method
The not high technical problem of existing expensive reagents, severe reaction conditions, yield.
Than bent intermediate (compound A), structure is as follows in the one seed sand library:
Thinking of the present invention is the N-Boc-D-4 can largely arrive on the market, and 4 '-biphenylalanines are starting material, with rice
Decarboxylation forms lactams, alkaline open loop after family name's acid condensation production 'beta '-ketoester, reduction eliminate ketone carbonyl, methylation, last ethyl esterified
And it sloughs Boc- and protects to obtain Sha Ku than bent intermediate (compound A).
Its synthetic route is as follows:
Technical solution of the present invention is as follows: synthetic method of the seed sand library than bent intermediate, comprising the following steps:
(1) N-Boc-D-4,4 '-biphenylalanine and Michaelis acid condensation production 'beta '-ketoester
N-Boc-4,4 '-biphenylalanines and Michaelis acid are under the action of condensing agent and catalyst DMAP, and condensation is washed, dry
It is dry, be concentrated to get compound 1.The condensing agent can be one of DCC, DIC, EDCI, HATU or other similar carbon
Imidodicarbonic diamide class condensing agent, preferably DCC.
(2) 'beta '-ketoester restores
Compound 1, which is dissolved in glacial acetic acid and methylene chloride, is added portionwise reducing agent, is stirred to react, through extraction, washing, drying, dense
Contracting obtains compound 2.Reducing agent used can be one of sodium borohydride, lithium borohydride or potassium borohydride, preferably hydroboration
Sodium.
(3) it methylates
Compound 2 is dissolved in organic solvent, and inorganic metal alkali and iodomethane is added.After being stirred to react, filtering, filtrate pours into water
In, solid, filtering, dry compound 3 is precipitated in stirring.Inorganic metal alkali used is potassium carbonate or cesium carbonate, preferably carbonic acid
Potassium;There is solvent to can be one of acetone, acetonitrile or DMF or their mixture, preferably acetone-DMF mixed solvent.
(4) decarboxylation and contracting ring
After compound 3 and toluene mixing, heating reflux reaction is concentrated to dryness to obtain compound 4 after cooling.
(5) isomerization under organic metal alkali effect
Compound 4 is dissolved in THF, and organic metal alkali is added dropwise after cooling.Continue after being stirred to react, be poured into water, stir, filters out solid
Body.Solid re-crystallizing in ethyl acetate, filtering, dry compound 5.Organic metal alkali used is LiHMDS, NaHMDS or LDA
One of, preferably LiHMDS.
(6) inorganic metal alkali open ring
Compound 5 is dissolved in THF, and after cooling down, and inorganic metal alkali is added.It is stirred to react.Water quenching on the rocks is gone out, ethyl acetate extraction,
Organic layer washing, drying, are concentrated to give compound 6.Inorganic metal alkali used is lithium hydroxide monohydrate, sodium hydroxide, hydrogen-oxygen
Change one of potassium or potassium carbonate, preferably lithium hydroxide monohydrate.
(7) Boc and the husky library of ethyl esterified production are taken off than bent intermediate (compound A)
Compound 6 is dissolved in ethyl alcohol and cooling, is passed through acidic catalyst HCl gas.It is stirred to react and is heated to reflux.It is dense after cooling
It is reduced to dry that solid, solid obtain compound A with ethyl acetate/ethyl alcohol recrystallization.Acidic catalyst used, which can be, is passed through HCl gas
Body can also be added dropwise thionyl chloride and obtain, preferably logical HCl gas.
Beneficial effects of the present invention: (1) the N-Boc-D-4,4 '-biphenylalanine that can largely arrive on the market is utilized
For starting material, it is condensed production 'beta '-ketoester with Michaelis acid, single step reaction just constructs required carbochain;(2) using having after methylating
The effect of machine metal base constructs second required chiral centre, avoids expensive chiral catalyst;(3) N-Boc's
In the presence of protection, using inorganic base, under mild conditions open loop, and latter step is deprotected and the ethyl esterified target that obtains produces
Object, optical purity is high, at low cost.Raw materials used at low cost, simple process, reaction condition requires common, the easy purifying of intermediate,
It is suitble to industrial mass production.
Specific embodiment
It is described further the present invention below by following embodiment, these embodiments should not be construed as to limit of the invention
System.
Embodiment 1:N-Boc- (R) -5- (2-- amino -3- (1,1 '-biphenyl -4- base) propoxyl group) -2,2- dimethyl -1,3- two
The preparation of six ring -4,6- diketone of oxygen
Be added in 3 liters of there-necked flask N-Boc-4,4 '-biphenylalanine (198 g, 0.58 mol), Michaelis acid (92 g,
0.64 mol) and methylene chloride (800mL), stirring and dissolving, and be cooled to 0 DEG C or so, be added portionwise DMAP (106 g,
0.86 mol), DCC(240 g, 1.16 mol are then added portionwise again).Reaction solution is after 0 ~ 5 DEG C is stirred to react 1 hour, room
Temperature is stirred overnight.Filtering, filter cake are washed with methylene chloride (800mL).Filtrate and washing lotion successively use unsaturated carbonate hydrogen after merging
Sodium, 1N dilute hydrochloric acid solution and protection saline solution respectively wash three times, and anhydrous sodium sulfate is dry, after concentration, adds ethyl acetate/petroleum ether
Volume ratio (1:1,800mL) mashing, filtering, dry compound 1(186 g, molar yield 69%, white solid).
In this embodiment, if DCC is replaced with DIC, EDCI, HATU or other similar carbon imidodicarbonic diamide class contractings
Mixture, remaining finally can also obtain compound 1, molar yield 50 ~ 69% with embodiment 1.
Embodiment 2:N-Boc- (S) -5- (2-- amino -3- (1,1 '-biphenyl -4- base) propyl) -2,2- dimethyl -1,3-
The preparation of dioxane -4,6- diketone
Compound 1(140 g, 0.3 mol are added in 3 liters of there-necked flask), glacial acetic acid (400mL) and methylene chloride (1.5
L), stirring and dissolving, and -5 DEG C or so are cooled to, sodium borohydride (22.7 g, 0.6 mol) is added portionwise, finishes within about 1 hour.
For reaction solution after -5 ~ 0 DEG C is stirred to react 3 hours, TLC analyzes fully reacting.Add 1L ice water quenching reaction, is separated after stirring organic
Layer, water layer are extracted once again with methylene chloride, successively use saturated sodium bicarbonate, 1N dilute hydrochloric acid solution and protection after merging organic layer
Saline solution respectively washs three times, and anhydrous sodium sulfate is dry, after concentration, ethyl acetate/petroleum ether volume ratio (1:2,800 mL) is added to beat
Slurry, filtering, dry compound 2(109 g, molar yield 80%, white solid).It is as follows through nuclear magnetic resonance measuring result:1H
NMR (400 MHz, CDCl3): δ 7.45 (m, 9H), 4.49 (br, 1H), 4.28 (m, 1H), 3.92 (m,
1H), 2.90 (m, 2H), 2.18 (m, 2H), 1.78 (s, 3H), 1.74 (s, 3H), 1.36 (s, 9H) liquid
Phase chromatograph-mass spectrometer coupling measurement result is as follows: LC-MS (ESI):m/z 454.00 [M+H]+。
In this embodiment, if sodium borohydride is replaced with lithium borohydride, potassium borohydride or other similar reduction
Agent, remaining finally can also obtain compound 2, molar yield 55 ~ 72% with embodiment 2.
Embodiment 3:N-Boc- (S)-5- (2-- amino-3- (1,1 '-biphenyl-4- base) propyl) trimethyl-1-2,2,5-,
The preparation of 3- dioxane -4,6- diketone
Compound 2(75.6 g, 0.167 mol are added in 2 liters of there-necked flask), acetone (400 mL) and DMF (400 mL),
Stirring and dissolving, and it is cooled to 0 DEG C or so, potassium carbonate (35 g, 0.25 mol) and iodomethane (36 g, 0.25 mol) is added.
Reaction solution is stirred overnight at room temperature after 0 DEG C is stirred to react 1 hour.Filtering, filter cake are washed with acetone (200 mL).Filtrate and
It is poured into after washing lotion in 2L water, solid, filtering, dry compound 3(66.3 g, molar yield 85%, pale yellow colored solid is precipitated in stirring
Body).It is as follows through nuclear magnetic resonance measuring result:1H NMR (400 MHz, CDCl3): δ 7.40 (m, 7H), 7.16 (m,
2H), 4.18 (m, 1H), 3.92 (m, 1H), 2.84 (m, 2H), 2.23 (m, 2H), 1.72 (s, 6H),
1.61 (s, 3H), 1.31 (s, 9H) liquid chromatograph mass spectrography measurement results are as follows: LC-MS (ESI):m/z
468.43 [M+H]+。
In this embodiment, if potassium carbonate is replaced with cesium carbonate;Acetone replaces with acetonitrile, DMF etc., remaining is the same as implementation
Example 3 finally can also obtain compound 3, molar yield 65 ~ 75%.
The preparation of embodiment 4:N-Boc- (S) -5- (1,1 '-biphenyl -4- ylmethyl) -3- methylpyrroline -2- ketone
Compound 3(66.3 g, 0.14 mol are added in 2 liters of there-necked flask) and toluene (400 mL), it stirs, heats back
Stream reaction 16 hours, is concentrated to dryness to obtain compound 4(50.7 g, yield ~ 100%, faint yellow solid after cooling).Through nuclear magnetic resonance
Measurement result is as follows:1H NMR (400 MHz, CDCl3): δ 7.40 (m, 9H), 4.30 (m, 1H), 3.52 (m,
0.5 H), 3.18 (m, 0.5 H), 2.74 (m, 0.5H), 2.63 (m, 0.5H), 2.5 (m, 1H), 2.17
(m, 1H), 1.51 (m, 9H), 1.18 (m, 3H) liquid chromatograph mass spectrography measurement results are as follows: LC-MS
(ESI): m/z 366.30 [M+H]+。
The preparation of embodiment 5:N-Boc- (3S, 5R) -5- (1,1 '-biphenyl -4- ylmethyl) -3- methylpyrroline -2- ketone
Compound 4(50.7 g, 0.14 mol are added in 2 liters of there-necked flask) and THF (400 mL), stirring and dissolving, and
- 78 DEG C or so are cooled to, is added dropwise LiHMDS (1.3 M tetrahydrofuran solutions, 120 mL, 0.156 mol), about 0.5 hour
It is added dropwise.Reaction solution is stirred to react 1 hour at -20 ~ -10 DEG C, is stirred overnight at room temperature.Reaction solution pours into 2L water, stirring analysis
Solid out.Solid is recrystallized with ethyl acetate (500 mL), filters, is dry that compound 5(42.8 g, molar yield 84% are light
Yellow solid), HPLC purity 98.9%.It is as follows through nuclear magnetic resonance measuring result:1H NMR (400 MHz, CDCl3): δ
7.40 (m, 9H), 4.25 (m, 1H), 3.18 (m, 1H), 2.63 (m, 1H), 2.5 (m, 1H), 2.17 (m,
1H), 1.51 (m, 9H), 1.18 (m, 3H) liquid chromatograph mass spectrography measurement results are as follows: LC-MS (ESI):m/z 366.24 [M+H]+。
In this embodiment, if LiHMDS is replaced with the organic metal alkalis such as NaHMDS, LDA, remaining with embodiment 5,
It finally can also obtain compound 5, molar yield 60 ~ 82%.
The preparation of embodiment 6:N-Boc- (2S, 4R) -4- amino -5- (1,1 '-biphenyl -4- base) -2 methyl valeric acid
Addition compound 5 (42.8 g, 0.12 mol) and THF (200 mL) in 1 liter of there-necked flask, stirring and dissolving, and
It is cooled to 0 DEG C or so, is added lithium hydroxide monohydrate (9.8 g, 0.23 mol).Reaction solution is stirred to react 3 at 0 ~ 20 DEG C
Hour.Add 1L ice water quenching reaction, ethyl acetate extraction, organic layer successively uses saturated sodium bicarbonate, 1N dilute hydrochloric acid solution and guarantor
Shield saline solution respectively washs three times, and anhydrous sodium sulfate is dry, is concentrated to give compound 6(40.7 g, molar yield 88%, white is admittedly
Body).It is as follows through nuclear magnetic resonance measuring result:1H NMR (400 MHz, DMSO-d6): δ 12.01 (s, 1H), 7.40
(m, 9H), 6.40 (m, 1H), 3.66 (br, 1H), 2.69 (m, 1H), 2.43 (m, 1H), 1.77 (m,
1H), 1.31 (m, 9H), 1.04 (m, 3H)。
In this embodiment, if lithium hydroxide monohydrate is replaced with sodium hydroxide, potassium hydroxide or potassium carbonate
Equal inorganic metals alkali, remaining finally can also obtain compound 6, molar yield 75 ~ 85% with embodiment 6.
Embodiment 7:(2S, 4R) -4- amino -5- (1,1 '-biphenyl -4- base) -2 methyl valeric acid carbethoxy hydrochloride (compound
A preparation)
Compound 6(40.7 g, 0.11 mol are added in 1 liter of there-necked flask) and ethyl alcohol (200 mL), stirring and dissolving, and
It is cooled to 0 DEG C or so, is passed through HCl gas to weight gain 40% or so.Reaction solution is heated to reflux 3 after being stirred to react 3 hours at 0 ~ 20 DEG C
Hour.Solid is concentrated to dryness to obtain after cooling, solid obtains compound A(29.3 g, molar yield with ethyl acetate/ethyl alcohol recrystallization
79%, hydrochloride, white solid).It is as follows through nuclear magnetic resonance measuring result:1H NMR (400 MHz, DMSO-d6): δ 8.29
(br, 3H), 7.40 (m, 9H), 6.40 (m, 1H), 4.01 (m, 2H), 3.45 (m, 1H), 3.11(m,
1H), 2.75 (m, 2H), 1.87 (m, 1H), 1.61 (m, 1H), 1.14 (m, 6H).Liquid chromatograph mass spectrography
Measurement result is as follows: LC-MS (ESI):m/z 312.49 [M+H]+。
In this embodiment, it is passed through HCl gas and replaces with dropwise addition thionyl chloride, compound 6 and thionyl chloride charged material weight
Than for 1:1.1,1:1.5 or 1:2, remaining finally can also obtain compound A, molar yield 70 ~ 75% with embodiment 7.
Claims (15)
1. a seed sand library is than the synthetic method of bent intermediate, it is characterized in that: the following steps are included:
(1) N-Boc-D-4,4 '-biphenylalanine and Michaelis acid are condensed to yield compound 1 under condensing agent effect;
(2) compound 1 is restored to obtain compound 2 with reducing agent;
(3) compound 2 is dissolved in organic solvent, under the action of inorganic metal alkali and iodomethane obtains compound 3;
(4) compound 3 heats decarboxylation in toluene solution and contracting ring obtains compound 4;
(5) isomerization of the compound 4 under organic metal alkali effect obtains compound 5;
(6) open loop under the action of inorganic metal alkali of compound 5 obtains compound 6;
(7) compound 6 is catalyzed to obtain compound A in ethanol by acidic catalyst;
Its synthetic route is as follows:
。
2. a seed sand according to claim 1 library is than the synthetic method of bent intermediate, it is characterized in that: step (1) described contracting
Mixture is one of DCC, DIC, EDCI, HATU or other similar carbon imidodicarbonic diamide class condensing agents.
3. a seed sand according to claim 2 library is than the synthetic method of bent intermediate, it is characterized in that: condensing agent is DCC.
4. a seed sand according to claim 1 library is than the synthetic method of bent intermediate, it is characterized in that: step (2) is used also
Former agent is one of sodium borohydride, lithium borohydride or potassium borohydride.
5. a seed sand according to claim 4 library is than the synthetic method of bent intermediate, it is characterized in that: reducing agent is hydroboration
Sodium.
6. a seed sand according to claim 1 library is than the synthetic method of bent intermediate, it is characterized in that: nothing used in step (3)
Machine metal base is potassium carbonate or cesium carbonate.
7. a seed sand according to claim 6 library is than the synthetic method of bent intermediate, it is characterized in that: inorganic metal alkali is carbon
Sour potassium.
8. a seed sand according to claim 1 library is than the synthetic method of bent intermediate, it is characterized in that: step (3) is used to be had
Solvent is one of acetone, acetonitrile or DMF or their mixture.
9. a seed sand according to claim 8 library is than the synthetic method of bent intermediate, it is characterized in that: organic solvent is third
Ketone-DMF mixed solvent.
10. a seed sand according to claim 1 library is than the synthetic method of bent intermediate, it is characterized in that: step (5) is used to be had
Machine metal base is one of LiHMDS, NaHMDS or LDA.
11. a seed sand according to claim 10 library is than the synthetic method of bent intermediate, it is characterized in that: organic metal alkali is
LiHMDS。
12. a seed sand according to claim 1 library is than the synthetic method of bent intermediate, it is characterized in that: nothing used in step (6)
Machine metal base is one of lithium hydroxide monohydrate, sodium hydroxide, potassium hydroxide or potassium carbonate.
13. a seed sand according to claim 12 library is than the synthetic method of bent intermediate, it is characterized in that: inorganic metal alkali is
Lithium hydroxide monohydrate.
14. a seed sand according to claim 1 library is than the synthetic method of bent intermediate, it is characterized in that: acid used in step (7)
Property catalyst be HCl gas or thionyl chloride.
15. a seed sand according to claim 14 library is than the synthetic method of bent intermediate, it is characterized in that: acidic catalyst used
Agent is HCl gas.
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